The Top 12 Advances in Vascular Medicine

8/3/2019 The Top 12 Advances in Vascular Medicine

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2004 by the INTERNATIONAL SOCIETY OF ENDOVASCULAR SPECIALISTS Available at www.jevt.org

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

1Zena and Michael A. Wiener Cardiovascular Institute and Marie-Josee andHenry R. Kravis Center for Cardiovascular Health, Mount Sinai School ofMedicine, New York, New York, USA. 2Department of Medicine, Division ofCardiovascular Medicine, Massachusetts General Hospital, Boston,Massachusetts, USA. 3Department of Medicine, Division of CardiovascularMedicine, Brigham and Womens Hospital, Boston, Massachusetts, USA.4Department of Medicine, Division of Cardiovascular Medicine, Mayo Clinic,Rochester, Minnesota, USA.

In the past decade, impressive strides have been made in the diagnosis and managementof atherosclerotic, aneurysmal, and thromboembolic diseases, thanks in large part to theexplosive growth in both vascular biology and clinical vascular medicine. We review whatwe consider to be the top 12 advances in this field: the discovery of nitric oxide, themetabolic syndrome, new thrombophilic disorders, therapeutic angiogenesis, endoluminaltreatment of chronic venous disease, and a variety of drugs, including sildenafil, cilostazol,low-molecular-weight heparins, oral direct thrombin inhibitors, clopidogrel, statins, andangiotensin-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, sildenafil, cilostazol, low-molecular-weight heparin,clopidogrel, ACE inhibitors, angiotensin-receptor blocking agents, statins

Address for correspondence and reprints: Jeffrey W. Olin, DO, Professor of Medicine, Director, Vas-cular Medicine, Mount Sinai School of Medicine, One Gustave L. Levy Place, Box 1033, New York, NY10029 USA. Fax: 1-212-241-5107; E-mail: [email protected]

There has been explosive growth in the fieldof vascular medicine over the last decade, en-compassing both vascular biology and clini-cal vascular medicine. Signs that this emerg-ing field is gaining recognition are reflectedin the following initiatives that have devel-oped over the last several years.

American College of Cardiology (ACC) Re-

vised Recommendations for Training inAdult Cardiovascular Medicine Core Car-

diology Training II (COCATS 2). Task Force

11: Training in Vascular Medicine and Pe-

ripheral Catheter-based Interventions.1

The ACC describes 3 levels of training in

vascular medicine for individuals complet-ing a cardiovascular medicine fellowship.Level 1 represents basic training that allfellows should receive to acquire a suffi-cient knowledge base to care for many pa-tients with vascular disease. Level 2 ismore extensive training for fellows whowish to develop special expertise in theevaluation and management of patients

with vascular diseases. Level 3 training isdesigned to develop expertise in noncor-onary catheter-based interventions.

ACC/American Heart Association (AHA)/American College of Physicians (ACP) Clin-ical Competence Statement on Vascular


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Medicine and Catheter-Based PeripheralVascular Interventions.2 The aim of thismultidisciplinary writing group was to de-velop recommendations for attaining and

maintaining the cognitive and technicalskills necessary for the competent perfor-mance of a specific cardiovascular service,procedure, or technology.

AHA Atherosclerotic Vascular DiseaseConference.3 This Special Writing Groupreviewed the current knowledge of athero-sclerotic vascular disease (excluding thecoronary arteries) to develop a strategy forincreasing awareness of atheroscleroticvascular disease among clinicians and toidentify important gaps in our knowledgethat require further clinical investigation.

The 6 major themes discussed were: (1)epidemiology,4 (2) risk factors,5 (3) patho-physiology,6 (4) diagnostic imaging,7 (5)decision making and medical therapy,8

and (6) revascularization.9

ACC/AHA Guidelines for the Managementof Peripheral Arterial Disease (PAD) (Low-er Extremity, Renal, Mesenteric, and Ab-dominal Aorta). This document is part ofthe ACC/AHA Get With the Guidelinesprogram. These guidelines primarily ad-dress the diagnosis and management ofthe atherosclerotic, aneurysmal, and

thromboembolic processes associatedwith peripheral arterial diseases. Multiplespecialties contributed to this extensiveevidence-based document, including car-diology, vascular medicine, vascular sur-gery, interventional radiology, and ne-phrology. This document should beavailable by March 2005.

Formation of the American Board of Vas-cular Medicine. The Society for VascularMedicine and Biology has succeeded inestablishing board certification in generaland interventional vascular medicine.

These exciting initiatives have come aboutbecause of the remarkable advances in vas-cular biology and clinical vascular medicine.

THE TOP 12 ADVANCES INVASCULAR MEDICINE

The Discovery of Nitric Oxide

In 1992, nitric oxide (NO) was named Mole-cule of the Year by Science.10 In 1998, 3 indi-

viduals received the Nobel Prize in Medicinefor their work related to NO.11 Robert F. Furch-gott, PhD, discovered that the endotheliumproduces an unknown signaling molecule

that makes vascular smooth muscle cells(SMC) relax. He named the molecule endo-thelium-derived relaxing factor (EDRF). LouisJ. Ignarro, PhD, using hemoglobin spectro-photometry, proved that EDRF was identicalto nitric oxide. Lastly, Ferid Murad, MD, PhD,demonstrated that nitroglycerin relaxes SMCsby releasing nitric oxide, a process that in-duces cyclic guanosine monophosphate pro-duction.

The endothelium, the largest organ in thebody, produces nitric oxide, which plays animportant role in preventing atherogenesis.

Adequate NO production by endothelial nitricoxide synthase is essential for endothelialfunction. Nitric oxide produced by endothelialcells regulates vascular tone (causing vaso-dilation) and inhibits platelet aggregation,leukocyte adherence, and SMC prolifera-tion.12,13 In addition, nitric oxide mediatesboth native and growth factorinduced angio-genesis.14

The properties of NO make it a vital mole-cule to both understand and utilize in clinicalvascular medicine. In particular, patients withknown cardiovascular disease or with risk fac-tors may benefit from improvements in en-dothelial function and restored NO produc-tion. In addition to treating hyperlipidemiaand hypertension, statins and angiotensin-converting enzyme (ACE) inhibitors, respec-tively, have been shown to enhance NO re-lease and improve endothelial function.1518

Exercise training also appears to improve NO-mediated vasodilatation even in patients withestablished coronary artery disease.19 It hasbeen repeatedly demonstrated that cardio-vascular outcomes improve very early after

the initiation of therapies that improve endo-thelial function, long before regression of ath-erosclerosis occurs. The effects of many ofthe current cardiovascular therapies appear tobe related to improvements seen with NOmodulation.

The Metabolic Syndrome

Although Dr. Gerald Reaven first describedthe metabolic syndrome and brought it to


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the 3-untranslated region of the prothrombin

gene.32 This mutation, which increases pro-

thrombin synthesis, is associated with a 3-

fold increase in the risk for venous thrombo-

sis. The prothrombin gene mutation is secondin frequency to the Leiden mutation. Approx-imately 5.5% of patients with venous throm-

bosis will harbor this disorder, and about

1.2% of individuals in the general population

will test positive for the defect.33 Others in-

vestigators have suggested that this mutation

is found in 5% to 15% of patients presenting

with venous thrombosis and about 15% of pa-

tients being investigated for thrombophilia.

The prothrombin gene mutation is also as-

sociated with thrombosis in unusual sites,

such as cerebral vein thrombosis and portalvein thrombosis.34

Sildenafil (Viagra)

In 1989, UK-92,480 (sildenafil citrate) was

developed by Pfizer scientists.35 Sildenafil, an

inhibitor of phosphodiesterase type 5, was

originally intended to be an antianginal med-

ication. In 1992, an early trial using sildenafil

for angina noted that some of the patients

had the side effect of erections. Between 1994

and 1997, 21 clinical trials demonstrated sig-nificant improvement in treating erectile dys-

function with sildenafil. In 1998, the Food and

Drug Administration (FDA) approved Viagra

(Pfizer, New York, NY, USA) as the first 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 first 5 months after the

launch. Recently, 2 new drugs have been re-

leased with similar mechanisms of action.Vardenafil (Levitra; GlaxoSmithKline, Phila-

delphia, PA, USA) can be given with food,

whereas Viagras absorption is sometimes im-

paired after feeding, and tadalafil (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 dys-

function and has received more than its share

of media coverage.38

Cilostazol

Cilostazol, a phosphodiesterase type-3 in-hibitor, is the only medication approved for

the treatment of claudication that has dem-onstrated proven efficacy. The mechanism ofaction for improving claudication is notknown; however, cilostazol does have anti-platelet activity, vasodilatory properties, andin vitro inhibition of vascular SMCs. It alsocauses a moderate increase in HDL cholester-ol levels and decreases triglyceride levels.39 Ina recently published meta-analysis of 8 ran-domized, double-blind, placebo-controlled tri-als, cilostazol increased maximal and pain-free walking distances by 50% and 67%,respectively.39 Cilostazol was superior to pla-

cebo in most studies performed to date.40Dawson et al.41 compared the efficacy andsafety of cilostazol (100 mg bid) to pentoxi-fylline (400 mg tid) and placebo in patientswith intermittent claudication. After 24 weeks,cilostazol significantly increased walking dis-tance compared to pentoxifylline and place-bo. Because cilostazol is a phosphodiesteraseinhibitor similar to milrinone, it is contraindi-cated (black box warning) in patients with ahistory of congestive heart failure or in pa-tients with an ejection fraction 40%.42,43

Therapeutic Angiogenesis

Numerous studies have attempted to usethis strategy of administering growth factorsto stimulate angiogenesis and bypass ob-structions in the coronary and peripheral cir-culation. The Therapeutic Angiogenesis withRecombinant Fibroblast Growth Factor-2 forIntermittent Claudication (TRAFFIC) trial com-pared an intra-arterial infusion of recombinantfibroblast growth factor-2 (rFGF-2) to placeboin patients with intermittent claudication.44 At

90 days, patients who received 1 dose of rFGF-2 had significantly improved peak walkingtime compared to those who received placebo.A repeat infusion at 30 days had no additionalbenefit. Despite these promising results, theRegional Angiogenesis with Vascular Endo-thelial Growth Factor (RAVE) trial demonstrat-ed no difference in peak walking time be-tween PAD patients who received a singleintramuscular injection of vascular endothe-


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lial growth factor (VEGF) in an adenovirusvector versus patients who received place-bo.45 Disparity in these randomized trialscould be explained by differences in the pa-

tients studied, the angiogenic growth factors,the vehicle used, or the mode of delivery.

Recently, a randomized pilot trial examinedthe efficacy and safety of intramuscular injec-tions of bone marrow mononuclear cells intothe legs of patients with chronic limb ische-mia.46 The hypothesis of this study was thatinjected marrow cells would supply endothe-lial progenitor cells, angiogenic growth fac-tors, and cytokines to enhance angiogenesis.Twenty-four weeks after implantation, PADpatients who received bone marrow cells hadsignificantly improved ankle-brachial index,transcutaneous oximetry, and peak walkingtime compared to controls.

A study evaluating developmental endothe-lial locus-1 (Del-1)47,48 in patients with claudi-cation showed no difference between thosereceiving active treatment compared to pla-cebo.48 Another using hypoxia-inducible fac-tor 1 alpha will be enrolling in the near futurefor patients with claudication.49 The future oftherapeutic angiogenesis is certainly chal-lenging, but with continued research it mayfind utility in treating PAD patients with dis-

abling claudication and critical limb ischemia.

Low-Molecular-Weight Heparin

There has been an enormous body of lit-erature regarding the use of low-molecular-weight heparin (LMWH) in the prevention andtreatment of venous thromboembolic diseas-es. Low-molecular-weight heparin may sim-plify the treatment of deep vein thrombosisand pulmonary embolism because LMWHscan be administered subcutaneously once ortwice 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 ac-tivate antithrombin. The major difference be-tween LMWHs and unfractionated heparin isthe relative inhibitory activity against throm-bin and factor Xa. The LMWHs have greateractivity against factor Xa, while unfractionat-ed heparin has similar activity against factorXa and thrombin.50 The main advantage of

this class of drug in treating deep vein throm-bosis and pulmonary embolism is that thedose is calculated based on body weight, sothe clinician can be assured that the patient is

adequately anticoagulated. This same as-sumption cannot be made with unfractionat-ed heparin. Multiple randomized prospectivetrials have demonstrated that the LMWHs areequal in efficacy to unfractionated heparin.5154 Other advantages of the LMWHs include agreater effect on thrombus regression55 andlower mortality56 compared to unfractionatedheparins. Lee et al.57 demonstrated a 52% rel-ative risk reduction in recurrent venousthromboembolic events in cancer patientsrandomized to 6 months of dalteparin therapycompared to those randomized to warfarin.There was no increased bleeding in the long-term dalteparin group.

Oral Direct Thrombin Inhibitors

Ximelagatran (Exanta; AstraZeneca Phar-maceuticals, Waltham, MA, USA) is an orallyadministered prodrug of the active-site directthrombin inhibitor melagatran. While there isonly 20% bioavailability, it is rapidly convert-ed to melagatran and levels peak in 2 hours.The half-life is 3 to 4 hours, therefore bid ad-

ministration is required. A randomized, dou-ble-blind trial comparing 7 to 12 days of oralximelagatran (24 or 36 mg bid starting themorning after surgery, with warfarin therapystarting the same evening) was conducted,assessing the primary endpoint of venousthromboembolism and all-cause mortality.Among the 1851 patients, the 36-mg bid doseof ximelagatran was superior to warfarin inreducing the primary endpoint (20.3% versus27. 6% , r el at ive r isk r educti on 26. 4% ,p0.003). There was no difference in bleedingcomplications.58,59 The Thrombin Inhibitor in

Venous Thromboembolism (THRIVE) III Inves-tigators evaluated 1233 patients with venousthromboembolism who had undergone 6months of anticoagulant therapy with either24 mg bid of ximelagatran or placebo. Theprimary endpoint of recurrent symptomaticvenous thromboembolism was confirmed in12 patients assigned to ximelagatran and 71patients assigned to placebo (hazard ratio0.16, 95% confidence interval 0.09 to 0.30,


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p0.001). There was an elevation of alanineaminotransferase to more than 3 times theupper limit of normal in 6.4% of the activetreatment group.60

Two atrial fibrillation trials demonstratedthat ximelagatran at a dose of 36 mg bid wasas effective as warfarin in preventing strokeand systemic embolic events (Stroke Prophy-laxis Using an Oral Thrombin Inhibitor in Atri-al Fibrillation [SPORTIF] III and V).61,62 Unfor-t unat el y, t he FDA panel has r ecentl y

recommended that ximelagatran not be ap-proved due to fatal liver toxicity in several pa-tients.

Nonetheless, the oral direct thrombin inhib-itors will change the way that venous throm-

boembolic disease and atrial fibrillation aremanaged by providing a fixed dosage of drugthat can be administered without monitoringblood levels and still provide the same degreeof safety and efficacy as warfarin.

Clopidogrel

Antiplatelet agents such as aspirin are in-dicated for secondary prevention in high-riskcardiovascular patients. The AntithromboticTrialists Collaboration (ATC), a meta-analysisof randomized antiplatelet therapy trials, con-cluded that antiplatelet agents reduce all car-

diovascular events in high-risk patients.63 Inthe 9214 PAD patients reviewed in the ATCmeta-analysis, antiplatelet drugs reduced se-rious vascular events by 23%.63 A similar re-duction was seen in patients with intermittentclaudication and among patients undergoing

surgical or endovascular procedures.63

Thienopyridine agents, such as ticlopidineand clopidogrel, inhibit the activation of plate-lets by adenosine diphosphate (ADP). Bothmedications have been investigated as an al-

ternative antiplatelet agent to aspirin in PADpatients. From the ATC, both drugs demon-strated an efficacy similar to aspirin in reduc-ing vascular events.64 Despite promising re-sults, the use of ticlopidine has been limitedby the occurrence of serious hematological

toxicities (neutropenia and thrombotic throm-bocytopenic purpura) and the need to take thedrug twice a day. Clopidogrel has demon-strated fewer adverse hematological effects

and is administered in a single daily dose of75 mg.40,64

The efficacy of clopidogrel has been direct-ly compared to aspirin in the Clopidogrel Ver-

sus Aspirin in Patients at Risk of IschaemicEvents (CAPRIE) trial.65 Of the 19,185 high-riskcardiovascular patients (recent MI, recent is-chemic stroke, PAD) recruited for the study,6452 patients had PAD. The patients were ran-domized to either clopidogrel (75 mg daily) oraspirin (325 mg daily). After 3 years, therewas an 8.7% relative risk reduction in MI,stroke, or cardiovascular death in the groupassigned to clopidogrel compared to aspirin.The PAD subgroup had the greatest benefit infavor of clopidogrel, with a 23.8% relative riskreduction over aspirin.65 These observationshas led some experts to recommend clopi-dogrel in all patients with PAD to reduce therisk of cardiovascular morbidity and mortality.In the Clopidogrel in Unstable Angina to Pre-vent Recurrent Events (CURE) trial, the addi-tion of clopidogrel to aspirin in patients withacute coronary syndrome without ST eleva-tion produced fewer major cardiovascularevents compared to aspirin alone.66 The com-bination of clopidogrel and aspirin versus as-pirin alone in a high-risk group of patients in-cluding those with PAD is currently underway

in the Clopidogrel for High AtherothromboticRisk and Ischemic Stabilization, Management,and Avoidance (CHARISMA) trial.

ACE Inhibitors and Angiotensin-Receptor Blocking Agents

Beyond the antihypertensive effects, ACEinhibitors, such as ramipril and perindopril,have been shown to benefit patients who areat high risk for cardiovascular events. Basedon the Heart Outcomes Prevention Evaluation(HOPE) study, patients with diabetes or evi-

dence of vascular disease plus one other car-diovascular risk factor who received ramiprilhad a 22% risk reduction of stroke, MI, anddeath compared to patients who received pla-cebo.67 The subgroup of patients with PADwho were treated with ramipril had a 27% rel-ative risk reduction in the primary endpointscompared to the placebo-treated group.68

From the European Trial on Reduction of Car-diac Events With Perindopril in Patients With


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Stable Coronary Artery Disease (EUROPA)study, 12,218 patients with stable coronaryheart disease were randomly assigned to per-indopril (8 mg daily) or placebo.69 After a

mean follow-up of 4.2 years, cardiovascularevents were significantly decreased in pa-tients treated with perindopril. All predefinedsubgroups, including the 883 patients whohad documented PAD, benefited from perin-dopril.69 Similar to ACE inhibitors, angioten-sin-receptor blockers (ARBs) have demon-strated cardiovascular benefits beyond theirantihypertensive properties. In particular,ARBs promote improved endothelial functionthrough increased nitric oxide bioavailabilityor decreased vascular inflammation.70,71 Pa-tients with high cardiovascular risks, includ-ing PAD, are likely to benefit from ARBs. An-giotension-receptor blocking agents, such aslosartan and candesartan, have clearly shownmorbidity and mortality benefits either aloneor in combination with ACE inhibitors, asdemonstrated in the Losaratan InterventionFor Endpoint reduction (LIFE) and the Can-desartan in Heart Failure Assessment of Re-duction in Mortality and Morbidity (CHARM)studies.72,73

Statins

Dyslipidemia is an important risk factor forall types of vascular disease. According toThird Report of the National Cholesterol Ed-ucation Program (NCEP) Expert Panel on De-tection, Evaluation, and Treatment of HighBlood Cholesterol in Adults (Adult TreatmentPanel [ATP] III), PAD is a coronary heart dis-ease risk equivalent and should have a pri-mary treatment goal of a low density lipopro-tein (LDL) level 100 mg/dL.21 After the LDLgoal is reached, the ATP III recommends thatHDL levels be modified but does not specify

a target goal for raising HDL.Numerous cardiovascular trials have dem-

onstrated that statin medications play a criti-cal role in primary and secondary cardiovas-cular prevention. In PAD patients, 2 trials haveshown a small improvement in claudicationsymptoms and walking distance in patientstreated with statins.74,75 Independent of cho-lesterol-lowering effects, statin use improvedwalking distance and speed in PAD patients.76

In a trial of 354 PAD patients, those receiving

atorvastatin (80 mg/d) for 12 months demon-

strated a significant improvement in pain-free

walking time (but not in the primary endpoint

of peak walking time) compared to placebo:8115 versus 398 seconds, respectively(p0.025).74 In addition, there was no differ-

ence 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 to-

tal 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 thesymptoms of claudication in patients with

PAD.

There has not been a trial exclusively look-

ing at the mortality benefit 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 significant risk reduction of fatal and

nonfatal MIs compared to patients treated

with placebo. In the LIPID trial, 10% of the pa-tients had a documented history of claudica-

tion.77 In a subgroup analysis of the Scandi-

navian Simvastatin Survival Study (4S), therisk of developing new or worsening inter-

mittent 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 dem-

onstrated a 24% risk reduction in first-time

cardiovascular events.79 The subgroup of pa-

tients with PAD had similar cardiovascular

benefits regardless of prior history of MI or

coronary heart disease. Interestingly, the HPSwas also the first study to demonstrate a de-

crease in vascular events regardless of base-

line LDL concentrations. In the subgroup of

patients whose LDL cholesterol levels were

100 mg/dL at baseline, there was a signifi-

cant reduction in major cardiovascular events

after treatment with simvastatin.79 Similar

findings were reported in the subgroup of pa-

tients with cerebrovascular disease.


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Endoluminal Therapy for the Treatmentof Chronic Venous Disease

The advent of two new minimally invasive

techniques for saphenous vein ablation hasgenerated considerable excitement. Radiofre-quency (RF) ablation or closure and endov-enous laser therapy (EVLT) employ a similarend mechanism (heat), have similar clinicalapplications, and have been utilized as office-based procedures under local anesthesia.

Radiofrequency requires a bloodless fieldand close vein wall contact with the probe tip,which is heated to 85 to 95C. Typical treat-ment time is 30 minutes. Nonthromboticclosure of the treated vein is the goal. Inpractice, thrombotic occlusion is common,

eventually leading to involution or, in somecases, recanalization. In a feasibility study of30 limbs treated in 27 patients and followedfor a mean of 9.6 months, 22 (73.3%) of thegreater saphenous veins remained throm-bosed. Three (10%) limbs developed new orrecurrent venous varicosities.80

EVLT, on the other hand, destroys the veinmore directly with fiber-tip temperatures500C, with dissipation of heat to 50C atthe adventitial level. Heat transfer occurs par-tially through blood, thereby requiring less in-tense 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 ab-lation procedures, successful occlusion of thegreater saphenous vein occurred in 98.2% ofpatients. Of 121 limbs at 2 years follow-up,113 (92.4%) have remained closed by duplexultrasound imaging.81,82

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