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REVIEW

The Top 12 Advances in Vascular Medicine


Jeffrey W. Olin, DO1; James Jang, MD1; Michael R. Jaff, DO2; Joshua A. Beckman, MD3; and Thom Rooke, MD4 and Michael A. Wiener Cardiovascular Institute and Marie-Josee and Henry R. Kravis Center for Cardiovascular Health, Mount Sinai School of Medicine, New York, New York, USA. 2Department of Medicine, Division of Cardiovascular Medicine, Massachusetts General Hospital, Boston, Massachusetts, USA. 3Department of Medicine, Division of Cardiovascular Medicine, Brigham and Womens Hospital, Boston, Massachusetts, USA. 4Department of Medicine, Division of Cardiovascular Medicine, Mayo Clinic, Rochester, Minnesota, USA.
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In the past decade, impressive strides have been made in the diagnosis and management of atherosclerotic, aneurysmal, and thromboembolic diseases, thanks in large part to the explosive growth in both vascular biology and clinical vascular medicine. We review what we consider to be the top 12 advances in this eld: the discovery of nitric oxide, the metabolic syndrome, new thrombophilic disorders, therapeutic angiogenesis, endoluminal treatment of chronic venous disease, and a variety of drugs, including sildenal, cilostazol, low-molecular-weight heparins, oral direct thrombin inhibitors, clopidogrel, statins, and angiotensin-converting enzyme inhibitors and angiotensin-receptor blocking agents. J Endovasc Ther 2004;11(Suppl II):II-21II-31

Key words: vascular medicine, vascular biology, peripheral artery disease, nitric oxide, metabolic syndrome, angiogenesis, sildenal, cilostazol, low-molecular-weight heparin, clopidogrel, ACE inhibitors, angiotensin-receptor blocking agents, statins

There has been explosive growth in the eld of vascular medicine over the last decade, encompassing both vascular biology and clinical vascular medicine. Signs that this emerging eld is gaining recognition are reected in the following initiatives that have developed over the last several years. American College of Cardiology (ACC) Revised Recommendations for Training in Adult Cardiovascular Medicine Core Cardiology Training II (COCATS 2). Task Force 11: Training in Vascular Medicine and Peripheral Catheter-based Interventions. 1 The ACC describes 3 levels of training in

vascular medicine for individuals completing a cardiovascular medicine fellowship. Level 1 represents basic training that all fellows should receive to acquire a sufcient knowledge base to care for many patients with vascular disease. Level 2 is more extensive training for fellows who wish to develop special expertise in the evaluation and management of patients with vascular diseases. Level 3 training is designed to develop expertise in noncoronary catheter-based interventions. ACC/American Heart Association (AHA)/ American College of Physicians (ACP) Clinical Competence Statement on Vascular

Address for correspondence and reprints: Jeffrey W. Olin, DO, Professor of Medicine, Director, Vascular Medicine, Mount Sinai School of Medicine, One Gustave L. Levy Place, Box 1033, New York, NY 10029 USA. Fax: 1-212-241-5107; E-mail: jeffrey.olin@msnyuhealth.org 2004 by the INTERNATIONAL SOCIETY
OF

ENDOVASCULAR SPECIALISTS

Available at www.jevt.org

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Medicine and Catheter-Based Peripheral Vascular Interventions.2 The aim of this multidisciplinary writing group was to develop recommendations for attaining and maintaining the cognitive and technical skills necessary for the competent performance of a specic cardiovascular service, procedure, or technology. AHA Atherosclerotic Vascular Disease Conference.3 This Special Writing Group reviewed the current knowledge of atherosclerotic vascular disease (excluding the coronary arteries) to develop a strategy for increasing awareness of atherosclerotic vascular disease among clinicians and to identify important gaps in our knowledge that require further clinical investigation. The 6 major themes discussed were: (1) epidemiology,4 (2) risk factors,5 (3) pathophysiology,6 (4) diagnostic imaging,7 (5) decision making and medical therapy,8 and (6) revascularization.9 ACC/AHA Guidelines for the Management of Peripheral Arterial Disease (PAD) (Lower Extremity, Renal, Mesenteric, and Abdominal Aorta). This document is part of the ACC/AHA Get With the Guidelines program. These guidelines primarily address the diagnosis and management of the atherosclerotic, aneurysmal, and thromboembolic processes associated with peripheral arterial diseases. Multiple specialties contributed to this extensive evidence-based document, including cardiology, vascular medicine, vascular surgery, interventional radiology, and nephrology. This document should be available by March 2005. Formation of the American Board of Vascular Medicine. The Society for Vascular Medicine and Biology has succeeded in establishing board certication in general and interventional vascular medicine. These exciting initiatives have come about because of the remarkable advances in vascular biology and clinical vascular medicine.

THE TOP 12 ADVANCES IN VASCULAR MEDICINE


The Discovery of Nitric Oxide
In 1992, nitric oxide (NO) was named Molecule of the Year by Science.10 In 1998, 3 indi-

viduals received the Nobel Prize in Medicine for their work related to NO.11 Robert F. Furchgott, PhD, discovered that the endothelium produces an unknown signaling molecule that makes vascular smooth muscle cells (SMC) relax. He named the molecule endothelium-derived relaxing factor (EDRF). Louis J. Ignarro, PhD, using hemoglobin spectrophotometry, proved that EDRF was identical to nitric oxide. Lastly, Ferid Murad, MD, PhD, demonstrated that nitroglycerin relaxes SMCs by releasing nitric oxide, a process that induces cyclic guanosine monophosphate production. The endothelium, the largest organ in the body, produces nitric oxide, which plays an important role in preventing atherogenesis. Adequate NO production by endothelial nitric oxide synthase is essential for endothelial function. Nitric oxide produced by endothelial cells regulates vascular tone (causing vasodilation) and inhibits platelet aggregation, leukocyte adherence, and SMC proliferation.12,13 In addition, nitric oxide mediates both native and growth factorinduced angiogenesis.14 The properties of NO make it a vital molecule to both understand and utilize in clinical vascular medicine. In particular, patients with known cardiovascular disease or with risk factors may benet from improvements in endothelial function and restored NO production. In addition to treating hyperlipidemia and hypertension, statins and angiotensinconverting enzyme (ACE) inhibitors, respectively, have been shown to enhance NO release and improve endothelial function.1518 Exercise training also appears to improve NOmediated vasodilatation even in patients with established coronary artery disease.19 It has been repeatedly demonstrated that cardiovascular outcomes improve very early after the initiation of therapies that improve endothelial function, long before regression of atherosclerosis occurs. The effects of many of the current cardiovascular therapies appear to be related to improvements seen with NO modulation.

The Metabolic Syndrome


Although Dr. Gerald Reaven rst described the metabolic syndrome and brought it to

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prominence in 1988, the true understanding of this syndrome has occurred in the last decade.20 There are several denitions of the metabolic syndrome, but the most widely accepted is that put forward by the National Cholesterol Education Programs Adult Treatment Panel III.21 The components of the metabolic syndrome include a blood pressure 130/85 mmHg, abdominal circumference 40 inches in men or 35 inches in women, fasting high density lipoprotein (HDL) 40 mg/dL in men and 50 mg/dL in women, fasting triglyceride concentration 150 mg/dL, and fasting plasma glucose concentration 110 mg/dL.21 Patients who have 3 or more of these components are diagnosed with metabolic syndrome. It is estimated that 45 million people in the US are affected by this condition.22 The importance of the metabolic syndrome is apparent when put into the context of diabetes and atherosclerosis. The metabolic syndrome can also be described as the insulin resistance syndrome because insulin resistance forms its cornerstone. There is a progressive increase in insulin resistance with increasing metabolic syndrome components.23 Insulin resistance is the central pathogenetic abnormality underlying type 2 diabetes mellitus. Patients with the metabolic syndrome have a much higher risk of developing diabetes and its attendant risks of microvascular diseases (retinopathy, nephropathy, and neuropathy) and macrovascular events (stroke, myocardial infarction [MI], and amputation).24 The metabolic syndrome also sits at the nexus between an acquired and inherited disease process. Many of the components of the metabolic syndrome are the result of behavior and are modiable by changes in lifestyle. Indeed, caloric restriction and increased exercise have been demonstrated to improve components of the syndrome (waist circumference, blood pressure, and lipid prole) and decrease the progression to frank diabetes mellitus.25 The other important pathological process activated by the metabolic syndrome is inammation, which is associated with the development and progression of atherosclerosis.26 Increasing levels of inammation, as measured by blood markers such as C-reac-

tive protein, predict incident cases of symptomatic atherosclerosis, including MI, stroke, and PAD.27 As the number of components of metabolic syndrome increases, so does the amount of systemic inammation.27 Large epidemiological and case-control studies have demonstrated that patients with metabolic syndrome have a 2 to 4-fold increase in the risk of MI and cardiovascular death.28 Because of the increase in risk, patients with metabolic syndrome should have their 10year risk of MI quantied, and patients in the high-risk subgroups should have their risk factors modied as aggressively as patients with type 2 diabetes mellitus to decrease cardiovascular morbidity and mortality.

New Thrombophilic Disorders


Factor V Leiden Mutation. In 1993, Dahlback and colleagues29 identied an abnormality in an unrecognized plasma cofactor present in some families with thrombophilia; this factor functions in concert with protein S to support the anticoagulation properties of activated protein C. Activated protein C resistance (APC-R) is the most common cause of familial thrombophilia. In most cases, APC-R is the result of a single mutation in the factor V gene (arginine 506 to glutamine 506) and is known as the factor V Leiden mutation. In this situation, factor V is resistant to inactivation by activated protein C. This defect is inherited in an autosomal dominant fashion and results in increased thrombogenicity. The prevalence of this mutation varies considerably among different populations (US, UK, and Canada: 6% to 7% of the population; Greece and Sweden: 14% to 15% of the population; Japan and Africa: 1% of the population).30 The relative risk of thrombosis is 3 to 4 times higher in those heterozygous for the factor V Leiden mutation and 80 times higher in those homozygous for the mutation. There is also an increased rate of venous thrombosis in individuals who have the factor V Leiden mutation and receive hormone replacement or oral contraceptive pills.31 Prothrombin 20210A Mutation. In 1996, the prothrombin gene mutation 20210A was identied as a defect resulting from adenine substitution for a guanine at nucleotide 20210 in

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the 3 -untranslated region of the prothrombin gene.32 This mutation, which increases prothrombin synthesis, is associated with a 3fold increase in the risk for venous thrombosis. The prothrombin gene mutation is second in frequency to the Leiden mutation. Approximately 5.5% of patients with venous thrombosis will harbor this disorder, and about 1.2% of individuals in the general population will test positive for the defect.33 Others investigators have suggested that this mutation is found in 5% to 15% of patients presenting with venous thrombosis and about 15% of patients being investigated for thrombophilia. The prothrombin gene mutation is also associated with thrombosis in unusual sites, such as cerebral vein thrombosis and portal vein thrombosis.34

Cilostazol
Cilostazol, a phosphodiesterase type-3 inhibitor, is the only medication approved for the treatment of claudication that has demonstrated proven efcacy. The mechanism of action for improving claudication is not known; however, cilostazol does have antiplatelet activity, vasodilatory properties, and in vitro inhibition of vascular SMCs. It also causes a moderate increase in HDL cholesterol levels and decreases triglyceride levels.39 In a recently published meta-analysis of 8 randomized, double-blind, placebo-controlled trials, cilostazol increased maximal and painfree walking distances by 50% and 67%, respectively.39 Cilostazol was superior to placebo in most studies performed to date.40 Dawson et al.41 compared the efcacy and safety of cilostazol (100 mg bid) to pentoxifylline (400 mg tid) and placebo in patients with intermittent claudication. After 24 weeks, cilostazol signicantly increased walking distance compared to pentoxifylline and placebo. Because cilostazol is a phosphodiesterase inhibitor similar to milrinone, it is contraindicated (black box warning) in patients with a history of congestive heart failure or in patients with an ejection fraction 40%.42,43

Sildenal (Viagra)
In 1989, UK-92,480 (sildenal citrate) was developed by Pzer scientists.35 Sildenal, an inhibitor of phosphodiesterase type 5, was originally intended to be an antianginal medication. In 1992, an early trial using sildenal for angina noted that some of the patients had the side effect of erections. Between 1994 and 1997, 21 clinical trials demonstrated signicant improvement in treating erectile dysfunction with sildenal. In 1998, the Food and Drug Administration (FDA) approved Viagra (Pzer, New York, NY, USA) as the rst oral medication for erectile dysfunction; as of 2001, more than 45 million prescriptions for Viagra had been written in more than 100 countries. More than 300,000 US physicians have prescribed Viagra, and sales exceeded $1 billion within the rst 5 months after the launch. Recently, 2 new drugs have been released with similar mechanisms of action. Vardenal (Levitra; GlaxoSmithKline, Philadelphia, PA, USA) can be given with food, whereas Viagras absorption is sometimes impaired after feeding, and tadalal (Cialis; Eli Lilly, Indianapolis, IN, USA) has a duration of action of 36 hours.36,37 This class of drugs has had a major impact on men with erectile dysfunction and has received more than its share of media coverage.38

Therapeutic Angiogenesis
Numerous studies have attempted to use this strategy of administering growth factors to stimulate angiogenesis and bypass obstructions in the coronary and peripheral circulation. The Therapeutic Angiogenesis with Recombinant Fibroblast Growth Factor-2 for Intermittent Claudication (TRAFFIC) trial compared an intra-arterial infusion of recombinant broblast growth factor-2 (rFGF-2) to placebo in patients with intermittent claudication.44 At 90 days, patients who received 1 dose of rFGF2 had signicantly improved peak walking time compared to those who received placebo. A repeat infusion at 30 days had no additional benet. Despite these promising results, the Regional Angiogenesis with Vascular Endothelial Growth Factor (RAVE) trial demonstrated no difference in peak walking time between PAD patients who received a single intramuscular injection of vascular endothe-

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lial growth factor (VEGF) in an adenovirus vector versus patients who received placebo. 45 Disparity in these randomized trials could be explained by differences in the patients studied, the angiogenic growth factors, the vehicle used, or the mode of delivery. Recently, a randomized pilot trial examined the efcacy and safety of intramuscular injections of bone marrow mononuclear cells into the legs of patients with chronic limb ischemia.46 The hypothesis of this study was that injected marrow cells would supply endothelial progenitor cells, angiogenic growth factors, and cytokines to enhance angiogenesis. Twenty-four weeks after implantation, PAD patients who received bone marrow cells had signicantly improved ankle-brachial index, transcutaneous oximetry, and peak walking time compared to controls. A study evaluating developmental endothelial locus-1 (Del-1)47,48 in patients with claudication showed no difference between those receiving active treatment compared to placebo.48 Another using hypoxia-inducible factor 1 alpha will be enrolling in the near future for patients with claudication.49 The future of therapeutic angiogenesis is certainly challenging, but with continued research it may nd utility in treating PAD patients with disabling claudication and critical limb ischemia.

this class of drug in treating deep vein thrombosis and pulmonary embolism is that the dose is calculated based on body weight, so the clinician can be assured that the patient is adequately anticoagulated. This same assumption cannot be made with unfractionated heparin. Multiple randomized prospective trials have demonstrated that the LMWHs are equal in efcacy to unfractionated heparin.51 54 Other advantages of the LMWHs include a greater effect on thrombus regression55 and lower mortality56 compared to unfractionated heparins. Lee et al.57 demonstrated a 52% relative risk reduction in recurrent venous thromboembolic events in cancer patients randomized to 6 months of dalteparin therapy compared to those randomized to warfarin. There was no increased bleeding in the longterm dalteparin group.

Oral Direct Thrombin Inhibitors


Ximelagatran (Exanta; AstraZeneca Pharmaceuticals, Waltham, MA, USA) is an orally administered prodrug of the active-site direct thrombin inhibitor melagatran. While there is only 20% bioavailability, it is rapidly converted to melagatran and levels peak in 2 hours. The half-life is 3 to 4 hours, therefore bid administration is required. A randomized, double-blind trial comparing 7 to 12 days of oral ximelagatran (24 or 36 mg bid starting the morning after surgery, with warfarin therapy starting the same evening) was conducted, assessing the primary endpoint of venous thromboembolism and all-cause mortality. Among the 1851 patients, the 36-mg bid dose of ximelagatran was superior to warfarin in reducing the primary endpoint (20.3% versus 27.6%, relative risk reduction 26.4%, p 0.003). There was no difference in bleeding complications.58,59 The Thrombin Inhibitor in Venous Thromboembolism (THRIVE) III Investigators evaluated 1233 patients with venous thromboembolism who had undergone 6 months of anticoagulant therapy with either 24 mg bid of ximelagatran or placebo. The primary endpoint of recurrent symptomatic venous thromboembolism was conrmed in 12 patients assigned to ximelagatran and 71 patients assigned to placebo (hazard ratio 0.16, 95% condence interval 0.09 to 0.30,

Low-Molecular-Weight Heparin
There has been an enormous body of literature regarding the use of low-molecularweight heparin (LMWH) in the prevention and treatment of venous thromboembolic diseases. Low-molecular-weight heparin may simplify the treatment of deep vein thrombosis and pulmonary embolism because LMWHs can be administered subcutaneously once or twice daily, and there is rarely a need for monitoring or dose adjustment. In addition, many patients can be treated as outpatients. Both LMWHs and unfractionated heparin activate antithrombin. The major difference between LMWHs and unfractionated heparin is the relative inhibitory activity against thrombin and factor Xa. The LMWHs have greater activity against factor Xa, while unfractionated heparin has similar activity against factor Xa and thrombin.50 The main advantage of

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p 0.001). There was an elevation of alanine aminotransferase to more than 3 times the upper limit of normal in 6.4% of the active treatment group.60 Two atrial brillation trials demonstrated that ximelagatran at a dose of 36 mg bid was as effective as warfarin in preventing stroke and systemic embolic events (Stroke Prophylaxis Using an Oral Thrombin Inhibitor in Atrial Fibrillation [SPORTIF] III and V).61,62 Unfortunately, the FDA panel has recently recommended that ximelagatran not be approved due to fatal liver toxicity in several patients. Nonetheless, the oral direct thrombin inhibitors will change the way that venous thromboembolic disease and atrial brillation are managed by providing a xed dosage of drug that can be administered without monitoring blood levels and still provide the same degree of safety and efcacy as warfarin.

Clopidogrel
Antiplatelet agents such as aspirin are indicated for secondary prevention in high-risk cardiovascular patients. The Antithrombotic Trialists Collaboration (ATC), a meta-analysis of randomized antiplatelet therapy trials, concluded that antiplatelet agents reduce all cardiovascular events in high-risk patients.63 In the 9214 PAD patients reviewed in the ATC meta-analysis, antiplatelet drugs reduced serious vascular events by 23%.63 A similar reduction was seen in patients with intermittent claudication and among patients undergoing surgical or endovascular procedures.63 Thienopyridine agents, such as ticlopidine and clopidogrel, inhibit the activation of platelets by adenosine diphosphate (ADP). Both medications have been investigated as an alternative antiplatelet agent to aspirin in PAD patients. From the ATC, both drugs demonstrated an efcacy similar to aspirin in reducing vascular events.64 Despite promising results, the use of ticlopidine has been limited by the occurrence of serious hematological toxicities (neutropenia and thrombotic thrombocytopenic purpura) and the need to take the drug twice a day. Clopidogrel has demonstrated fewer adverse hematological effects

and is administered in a single daily dose of 75 mg.40,64 The efcacy of clopidogrel has been directly compared to aspirin in the Clopidogrel Versus Aspirin in Patients at Risk of Ischaemic Events (CAPRIE) trial.65 Of the 19,185 high-risk cardiovascular patients (recent MI, recent ischemic stroke, PAD) recruited for the study, 6452 patients had PAD. The patients were randomized to either clopidogrel (75 mg daily) or aspirin (325 mg daily). After 3 years, there was an 8.7% relative risk reduction in MI, stroke, or cardiovascular death in the group assigned to clopidogrel compared to aspirin. The PAD subgroup had the greatest benet in favor of clopidogrel, with a 23.8% relative risk reduction over aspirin.65 These observations has led some experts to recommend clopidogrel in all patients with PAD to reduce the risk of cardiovascular morbidity and mortality. In the Clopidogrel in Unstable Angina to Prevent Recurrent Events (CURE) trial, the addition of clopidogrel to aspirin in patients with acute coronary syndrome without ST elevation produced fewer major cardiovascular events compared to aspirin alone.66 The combination of clopidogrel and aspirin versus aspirin alone in a high-risk group of patients including those with PAD is currently underway in the Clopidogrel for High Atherothrombotic Risk and Ischemic Stabilization, Management, and Avoidance (CHARISMA) trial.

ACE Inhibitors and AngiotensinReceptor Blocking Agents


Beyond the antihypertensive effects, ACE inhibitors, such as ramipril and perindopril, have been shown to benet patients who are at high risk for cardiovascular events. Based on the Heart Outcomes Prevention Evaluation (HOPE) study, patients with diabetes or evidence of vascular disease plus one other cardiovascular risk factor who received ramipril had a 22% risk reduction of stroke, MI, and death compared to patients who received placebo.67 The subgroup of patients with PAD who were treated with ramipril had a 27% relative risk reduction in the primary endpoints compared to the placebo-treated group. 68 From the European Trial on Reduction of Cardiac Events With Perindopril in Patients With

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Stable Coronary Artery Disease (EUROPA) study, 12,218 patients with stable coronary heart disease were randomly assigned to perindopril (8 mg daily) or placebo.69 After a mean follow-up of 4.2 years, cardiovascular events were signicantly decreased in patients treated with perindopril. All predened subgroups, including the 883 patients who had documented PAD, beneted from perindopril.69 Similar to ACE inhibitors, angiotensin-receptor blockers (ARBs) have demonstrated cardiovascular benets beyond their antihypertensive properties. In particular, ARBs promote improved endothelial function through increased nitric oxide bioavailability or decreased vascular inammation.70,71 Patients with high cardiovascular risks, including PAD, are likely to benet from ARBs. Angiotension-receptor blocking agents, such as losartan and candesartan, have clearly shown morbidity and mortality benets either alone or in combination with ACE inhibitors, as demonstrated in the Losaratan Intervention For Endpoint reduction (LIFE) and the Candesartan in Heart Failure Assessment of Reduction in Mortality and Morbidity (CHARM) studies.72,73

Statins
Dyslipidemia is an important risk factor for all types of vascular disease. According to Third Report of the National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel [ATP] III), PAD is a coronary heart disease risk equivalent and should have a primary treatment goal of a low density lipoprotein (LDL) level 100 mg/dL.21 After the LDL goal is reached, the ATP III recommends that HDL levels be modied but does not specify a target goal for raising HDL. Numerous cardiovascular trials have demonstrated that statin medications play a critical role in primary and secondary cardiovascular prevention. In PAD patients, 2 trials have shown a small improvement in claudication symptoms and walking distance in patients treated with statins.74,75 Independent of cholesterol-lowering effects, statin use improved walking distance and speed in PAD patients.76

In a trial of 354 PAD patients, those receiving atorvastatin (80 mg/d) for 12 months demonstrated a signicant improvement in pain-free walking time (but not in the primary endpoint of peak walking time) compared to placebo: 81 15 versus 39 8 seconds, respectively (p 0.025).74 In addition, there was no difference in quality of life as measured by several questionnaires. In another study, simvastatin (40 mg/d) was given to 43 PAD patients for 6 months; the patients receiving simvastatin showed an increase in mean pain-free and total walking distance and also an improvement in the ABI.75 The effect of statins in each of these studies was small. While statins should be used to lower cardiovascular risk, they should not be a primary treatment for the symptoms of claudication in patients with PAD. There has not been a trial exclusively looking at the mortality benet of statins in PAD patients. In the Long-term Intervention With Pravastatin in Ischaemic Disease (LIPID) trial, all patients treated with pravastatin (40 mg/d) had a signicant risk reduction of fatal and nonfatal MIs compared to patients treated with placebo. In the LIPID trial, 10% of the patients had a documented history of claudication.77 In a subgroup analysis of the Scandinavian Simvastatin Survival Study (4S), the risk of developing new or worsening intermittent claudication was reduced by 38% in the group treated with simvastatin for 72 months.78 In the largest study evaluating the effects of statin use (simvastatin 40 mg/d) in high-risk patients (Heart Protection Study [HPS]), patients assigned to simvastatin demonstrated a 24% risk reduction in rst-time cardiovascular events.79 The subgroup of patients with PAD had similar cardiovascular benets regardless of prior history of MI or coronary heart disease. Interestingly, the HPS was also the rst study to demonstrate a decrease in vascular events regardless of baseline LDL concentrations. In the subgroup of patients whose LDL cholesterol levels were 100 mg/dL at baseline, there was a signicant reduction in major cardiovascular events after treatment with simvastatin.79 Similar ndings were reported in the subgroup of patients with cerebrovascular disease.

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Endoluminal Therapy for the Treatment of Chronic Venous Disease


The advent of two new minimally invasive techniques for saphenous vein ablation has generated considerable excitement. Radiofrequency (RF) ablation or closure and endovenous laser therapy (EVLT) employ a similar end mechanism (heat), have similar clinical applications, and have been utilized as ofcebased procedures under local anesthesia. Radiofrequency requires a bloodless eld and close vein wall contact with the probe tip, which is heated to 85 to 95 C. Typical treatment time is 30 minutes. Nonthrombotic closure of the treated vein is the goal. In practice, thrombotic occlusion is common, eventually leading to involution or, in some cases, recanalization. In a feasibility study of 30 limbs treated in 27 patients and followed for a mean of 9.6 months, 22 (73.3%) of the greater saphenous veins remained thrombosed. Three (10%) limbs developed new or recurrent venous varicosities.80 EVLT, on the other hand, destroys the vein more directly with ber-tip temperatures 500 C, with dissipation of heat to 50 C at the adventitial level. Heat transfer occurs partially through blood, thereby requiring less intense vein compression. Digital compression over the conveniently lighted tip is adequate. Treatment times average less than 7 minutes. In a study of 499 greater saphenous vein ablation procedures, successful occlusion of the greater saphenous vein occurred in 98.2% of patients. Of 121 limbs at 2 years follow-up, 113 (92.4%) have remained closed by duplex ultrasound imaging.81,82

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