Author''s Accepted Manuscript

Table of Contents Foreword Biographical Sketches Introduction Interventional cardiologist as the vascular expert Aortic Aneurysms and Dissection Abdominal Aortic Aneurysm Thoracic an

Increasing Role of Interventional Cardiologists for

Peripheral Vascular Disease

Tonga Nfor MD, MSPH, Suhail Allaqaband MD,

FACC, FCCP, FSCAI, Tanvir Bajwa MD, FACC,

FSCAI

PII: S0146-2806(14)00037-1

DOI: http://dx.doi.org/10.1016/j.cpcardiol.2014.05.003

Reference: YMCD276

To appear in: Curr Probl Cardiol

Cite this article as: Tonga Nfor MD, MSPH, Suhail Allaqaband MD, FACC, FCCP,FSCAI, Tanvir Bajwa MD, FACC, FSCAI, Increasing Role of InterventionalCardiologists for Peripheral Vascular Disease, Curr Probl Cardiol, http://dx.doi.org/10.1016/j.cpcardiol.2014.05.003

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Increasing Role of Interventional Cardiologists for Peripheral Vascular Disease

Tonga Nfor, MD, MSPH,

Suhail Allaqaband, MD, FACC, FCCP, FSCAI, and

Tanvir Bajwa, MD, FACC, FSCAI

Aurora Cardiovascular Services, Aurora Sinai/Aurora St Luke’s Medical Centers, University of Wisconsin School of Medicine and Public Health, Milwaukee, Wisconsin

Brief Title: Nfor et al – Role of interventional cardiologist in PVD

Financial Support: None

Disclosure Statement: Nothing to disclose

Address for Correspondence:

Tanvir Bajwa, MD, FACC, FSCAI

Aurora Cardiovascular Services

2801 W Kinnickinnic River Parkway, #840

Milwaukee, WI 53215

(414) 649-3909

(414) 649-3551 (fax)

publishing2@aurora.org 

Table of Contents

Foreword

Biographical Sketches

Introduction

Interventional cardiologist as the vascular expert

Aortic Aneurysms and Dissection

Abdominal Aortic Aneurysm

Thoracic and Thoracoabdominal Aortic Aneurysms

Aortic Dissection

Carotid and Vertebral Artery Disease

Percutaneous Treatment of Carotid Artery Disease

Vertebral Artery Disease

Subclavian and Brachiocephalic Artery Disease

Renal Artery Disease

Disease of the Celiac and Mesenteric Arteries

Lower Extremity Arterial Disease

Revascularization for Critical Limb Ischemia

Endovascular Treatment of Acute Limb Ischemia

Endovascular Treatment of Suprainguinal Disease

Endovascular Treatment of Femoropopliteal Disease

New Drug-Eluting Technologies for Femoropopliteal Disease

Endovascular Treatment of Infrapopliteal Disease

Adjuvant Therapies for Calcified Lesions and Chronic Total Occlusions

Percutaneous Treatments for Venous Occlusive Disease

Deep Venous Thrombosis of Lower Extremities

Catheter-directed Thrombolysis

Pharmacomechanical Thrombolysis

May-Thurner Syndrome

Inferior Vena Cava Filters

Veno-Occlusive Disease of Upper Extremities

Renal Denervation Therapy for Resistant Hypertension

Conclusion

References

Abstract

Improvements in the design of endovascular devices and technical skill of interventionalists have opened new possibilities for patients with a wide range of peripheral vascular diseases (PVD) In lower extremity peripheral artery disease, percutaneous treatments have become the predominant revascularization strategy for simple and complex lesions Newer

generations of stents and drug-coated balloons have demonstrated strong potential in treatment of femoropopliteal and infrainguinal diseases One of the most dramatic

advances in the recent past has been endovascular repair of thoracic and abdominal aortic aneurysms, which has become the preferred approach in lieu of open surgical repair

Contemporary trials have established the safety and effectiveness of carotid stenting in selected patients with severe stenosis Endovascular treatments for venous occlusive disease have long been underutilized, but their effectiveness is being increasingly recognized This review will cover new endovascular procedures performed by interventional cardiologists for PVD

Glossary of Abbreviations

AAA = abdominal aortic aneurysm

CAS = carotid artery stenting

CDT = catheter-directed thrombolysis

CEA = carotid endarterectomy

CI = confidence interval

DCB = drug-coated balloon

DES = drug-eluting stents

EVAR = endovascular abdominal aneurysm repair

PVD = peripheral vascular disease

SVC = superior vena cava

TASC = Trans-Atlantic Inter-Society Consensus

TEVAR = thoracic endovascular aneurysm repair

Introduction

Peripheral vascular disease (PVD) is a heterogeneous group of disorders that affect the

extracardiac circulatory system including arteries, veins and lymphatics Arterial atherosclerotic disease makes up the bulk of PVD disorders, but venous disorders of the lower extremities can cause significant morbidity Venous disorders manifest as veno-occlusive disease most

commonly from thrombosis or extrinsic compression, or as venous insufficiency with stasis in the lower extremities On the arterial side, PVD can involve arteries in the lower or upper

extremities, aorta and carotid, renal and mesenteric arteries Current nomenclature approved by professional societies is peripheral artery disease (PAD) for a disease of the lower and upper extremities exclusively However, in routine clinical practice, PAD is still used loosely to also include diseases of the aorta and carotid, renal and mesenteric arteries.1 The prevalence of PAD

is high among adult patients and increases with age In general medical practice using routine ankle-brachial index screening, PAD was found in 19.8% of men and 16.8% of women 65 years

or older.2

A key principle in the care of patients with atherosclerotic PAD in any one vascular territory

is to approach this as a marker of systemic atherosclerosis Large multinational registries have demonstrated that 50-60% of patients with established PAD also have cerebrovascular or

coronary disease.3,4 Patients with PAD have twice the risk of all-cause mortality and other major adverse cardiac events as those with matched Framingham risk scores but no PAD.5 The

management of patients with PVD requires a comprehensive approach that goes beyond

correcting the local anatomical abnormality of the vessel to include aggressive treatment for atherosclerosis to prevent cardiovascular mortality and morbidity, relieving pain and preserving functional status as well as preventing tissue or limb loss This often requires a multidisciplinary approach involving providers in different specialties Different experts with training in

interventional cardiology, interventional radiology or vascular surgery perform invasive

procedures to treat PVD The physician that manages PVD is required to have a broad

understanding of atherosclerotic disease and the cardiovascular or cerebrovascular mortality and morbidity associated with it Long-term patient follow-up and treatment is essential to prolong survival and maintain quality of life

Interventional Cardiologist as the Vascular Expert

Sample case: A 79-year-old man with coronary artery disease, PAD, critical aortic valve stenosis and left ventricular ejection fraction of 30% was transferred from an outside hospital to our institution with non-ST-segment elevation myocardial infarction, cardiogenic shock and

pulmonary edema He had already been turned down by two surgeons for surgical aortic valve replacement He was taken to the catheterization laboratory with the intention of percutaneous coronary revascularization, aortic valvuloplasty and intra-aortic balloon pump to bail him out of shock Coronary angiography showed acute subtotal occlusion of mid-left anterior descending artery The intra-aortic balloon pump required an 8 Fr sheath and valvuloplasty required a 12 Fr sheath, both of which could not be placed due to severe bilateral iliac stenosis The common iliac arteries were revascularized with kissing stents The intra-aortic balloon pump was then placed from the left common femoral artery and the left anterior descending artert was successfully stented via a sheath in the right common femoral artery Then the sheath in the right common femoral artery was upsized to 12 Fr and aortic valvuloplasty was performed Hemodynamics stabilized, pressors and inotropes were weaned off and the patient was extubated after 24 hours

He underwent successful transcatheter aortic valve replacement via femoral approach a week later and was discharged home

Interventional cardiologists have become more involved in managing PVD as medical

therapies, invasive techniques and devices improve Unlike other specialties, the interventional cardiologist’s background in internal medicine and general cardiology provides expertise in both the medical and invasive management of PVD that is uncommon for other specialties As the population ages and patients develop more advanced cardiac and peripheral disease,

interventional cardiologists have adapted their ability in manipulating large sheaths and devices for procedures like transcatheter aortic valve replacements, placement of intra-aortic balloon pumps and percutaneous left ventricular assist devices, and endovascular repair of aortic or thoracic aneurysms In an analysis of admissions for PAD in the United States between 1996 and

2005, open surgical procedures decreased by 6.6% per year while endovascular procedures increased by 4.8% per year (Fig 1).6 This corresponded with a decrease in acute admissions for PAD by 4.3% per year and major amputations by 6.4% per year during the same period

Endovascular procedures for PVD are performed by interventional radiologists, vascular

surgeons and interventional cardiologists with the role of the latter constantly increasing Data from the National Inpatient Sample showed that the number of endovascular procedures done for PVD by interventional radiologists decreased six-fold between 1998 and 2005, the share done by vascular surgeons doubled and by interventional cardiologists tripled.7 More recent Medicare data, including both inpatient and outpatient lower extremity endovascular interventions, show interventional cardiologists leading the pack with 37.6% of procedures, followed by vascular surgeons with 36.7%, interventional radiologists with 24.4% and others 1.3%.8

This paper presents an up-to-date review of techniques, devices and outcomes from

endovascular interventions for PVD that are performed by interventional cardiologists

Endovascular treatments for diseases of the aorta, carotid, renal, mesenteric, upper and lower arteries as well as venous occlusive disease will be discussed

Aortic Aneurysms and Dissection

Aortic aneurysm and aortic dissection have similar risk factors as atherosclerotic disease in other arterial territories; however, uncontrolled hypertension and genetic predisposition may play

a disproportionately stronger role in pathogenesis The identification of genes associated with aortic aneurysms and dissection is a fast-growing area of research Medical treatment involves controlling blood pressure and heart rate, use of statins and antiplatelet therapy When repair of the aortic aneurysm is indicated, endovascular repair is fast growing as the preferred alternative

to open surgical repair

Abdominal Aortic Aneurysm

The prevalence of abdominal aortic aneurysm (AAA) in the general population is about 1.3%

in men and 0.1% in women 45 to 55 years old, increasing to 12.5% in men and 5.2% in women older than 75 years.9 Patients with AAA are usually asymptomatic, and the rationale for repair is

to avoid rupture since 64% of patients with ruptured AAA die before reaching the hospital.10Repair of stable AAA is recommended when the maximum diameter exceeds 5 cm Several trials have shown that endovascular repair of abdominal aortic aneurysm (EVAR) confers lower short-term mortality and morbidity than open surgical repair but long-term survival beyond two years after repair is similar (Table 1).11-15 This is because most patients are elderly and long-term survival after repair of AAA is driven more by comorbidities than aorta-specific complications

This emphasizes the need for continuous, aggressive management of atherosclerotic disease to prevent cardiac and cerebrovascular mortality In today’s practice, EVAR has become the

preferred method to repair AAA whenever technically feasible Analysis of the Medicare

Standard Analytic File made up of a random 5% sample of all claims from 2003 to 2007 found that EVAR made up 84% of all claims for repair of AAA, while open surgical repair constituted 16% (Fig 2).15

The choice between endovascular and surgical repair should be based on several factors, like anatomical feasibility, surgical and anesthetic risk, local technical expertise, patient preference and compliance with long-term follow-up The suitability of peripheral vascular access may be a limiting factor for endovascular aneurysm repair The standard approach is to use the common femoral arteries, which should be able to accommodate 14 to 24 Fr sheaths depending of the size and type of endoprosthesis used (Fig 3) Femoral access would not be advised for patients whose common femoral artery lumen is <6 mm in diameter When a sheath size smaller than 20 Fr is used, femoral access can be entirely transcutaneous without surgical cutdown, and the access site repaired using a variety of large vessel closure devices In patients with unsuitable femoral access, alternative access can be obtained using a surgical conduit to the common iliac artery or directly to the aorta In general, EVAR may not be ideal if the aneurysm involves the origin of the renal arteries or there is <10 mm of infrarenal landing zone, significant thrombus around the landing zone or significant angulation or calcification of the landing zone However, new

endograft designs and interventional techniques have been developed to tackle these difficult anatomies, and these advances have expanded the scope of patients who may successfully

undergo EVAR Such advances include, but are not limited to, use of suprarenal fixation,

fenestrated and branched grafts that ensure perfusion of aortic branches, and chimney technique

to preserve renal perfusion

Thoracic and Thoracoabdominal Aortic Aneurysms

Thoracic aortic aneurysms and thoracoabdominal aortic aneurysms represent about 30% of hospital admissions for aortic disease, of which about a third are dissections and rupture.16

However, most patients with thoracic aortic aneurysms are asymptomatic, and repair is indicated when the diameter exceeds 5.5 cm or rate of expansion is more than 0.5 cm per year A lower threshold (4.5 to 5 cm) for repair is recommended in patients with genetic syndromes like

Marfan, Loeys-Dietz or Ehlers-Danlos The use of thoracic endovascular aneurysm repair

(TEVAR) for descending thoracic and thoracoabdominal aneurysms has been steadily

increasing Analysis of Medicare claims showed that the use of TEVAR increased from zero in

1998 to 5.8 per 100,000 Medicare beneficiaries in 2007, while the rate of open surgical repair remained relatively stable around 10 to 12 per 100,000 beneficiaries.17 The basic principles guiding successful TEVAR are:

• adequate vascular access that can accommodate large bore devices;

• good landing zones with healthy aorta proximal and distal to the aneurysm to obtain good seal and avoid endoleaks;

• appropriate sizing of the endograft in its proximal and distal diameter to obtain seal and its length to completely cover the aneurysm;

• ensuring that the branches of the aortic arch and renal arteries are not covered by the endograft, otherwise a debranching procedure should be done; and

• minimizing the risk of spinal ischemia from occluding spinal arteries originating from the descending thoracic aorta Spinal perfusion pressure can be maintained by keeping

moderately elevated mean aortic pressure and low spinal fluid pressure via a lumbar drain

Multiple studies comparing TEVAR with open surgical repair of descending thoracic aortic aneurysms have shown lower mortality and morbidity associated with TEVAR making TEVAR the preferred method of repair when anatomically feasible.16 This is illustrated in a meta-analysis

of 42 studies comparing TEVAR with open repair in 5,888 patients with descending thoracic aortic aneurysms.18 Thirty-day mortality was 5.8% for TEVAR compared to 13.9% for open repair, p<0.0001 However, after the second year post-repair there was no difference in all-cause mortality between TEVAR and open repair,; 23% vs 24.8%, respectively, p=0.65 TEVAR also had lower incidence of neurologic complications like stroke and paraplegia at 8.9% compared to open repair at 18.7%, p<0.001 In addition, TEVAR had fewer cardiac complications and

transfusions, lower incidence of renal failure and pneumonia, and shorter hospital length of stay than open repair Repeat intervention rates were similar between TEVAR (8.1%) and open repair (9.1%), p=0.95

We advocate management of all patients considered for thoracic aorta repair by a vascular team made up of interventional cardiologist and vascular or cardiothoracic surgeon Iliofemoral access is the preferred approach, but when the vessels are inadequate the direct aortic or left subclavian arterial access via minithoracotomy have been used When there is concern that the left subclavian and common carotid artery will need to be covered to get a good proximal

landing zone, surgical debranching should be performed such as a right-to-left carotid or

subclavian bypass or transposition of the left subclavian artery onto the common carotid prior to TEVAR (Fig 4)

Aortic Dissection

Aortic dissection is an acute disruption of the aortic media layer such that the layers become separated along the long axis of the aorta For the purposes of clinical management, dissection is considered a continuum of presentations from penetrating aortic ulcer and intramural hematoma

as less severe forms to complete dissection with a false lumen within the aortic wall as the more severe, immediately life-threatening form About 40% of patients with dissection die suddenly and an additional 20% die perioperatively.19 Initial management for all forms of dissection involves heart rate and blood pressure control with titrated intravenous beta blockers as first-line drug, pain control and avoidance of antithrombotics All patients with aortic dissection should have an urgent cardiothoracic surgical consultation Urgent surgical repair is the definitive

treatment in Stanford type A dissections Initial medical treatment only is recommended for type

B dissections, but complications like refractory pain, rupture, end organ hypoperfusion,

expansion of aneurysm or extension of dissection are definite indications for repair

Endovascular repair for dissections of the descending aorta is technically similar to TEVAR for descending thoracic aneurysms discussed previously The goal is to seal the entry sites into the dissection plane to prevent extension of the dissection and cause thrombosis within the dissection flap leading to remodeling and shrinkage of the dissected descending aorta TEVAR has emerged

as the treatment of choice for complicated type B dissections when technically feasible

Contrary to previous practice, a recent groundbreaking randomized controlled trial suggests that TEVAR may confer lower long-term mortality and morbidity than medical treatment alone

in patients with uncomplicated Sanford type B dissections In the INSTEAD-XL (Investigation

of Stent Grafts in Aortic Dissection with extended length of follow-up) trial, 140 patients with

stable type B aortic dissections were randomized to optimal medical therapy plus TEVAR or optimal medical therapy alone.20 There was a biphasic effect on mortality Within the first two years after randomization there was higher all-cause mortality in the TEVAR group than medical therapy group (11.1% vs 2.1%), but this was not statistically significant (p=0.08) Between years two and five the mortality in the TEVAR group was zero vs 16.9% in the medical therapy

group, p=0.0003 Overall, during the six-year study period mortality was significantly lower in the TEVAR group than optimal medical therapy group (hazard ratio [HR] 0.33 (95% confidence interval [CI] 0.12-0.91), p=0.03) The late deaths in the medical therapy group were due to complications from progression of aortic disease, which did not occur in the TEVAR group

Carotid and Vertebral Artery Disease

Endovascular management of carotid and vertebral artery disease falls within the scope of practice of interventional cardiologists The purpose of revascularization is to prevent the

morbidity and mortality associated with stroke due to stenosis, atheroemboli or, less commonly, dissection Aggressive medical therapy with antiplatelets, statins, blood pressure and other risk factor control is the primary treatment for carotid disease Aspirin is the first-line antiplatelet drug, but aspirin plus extended-release dipyridamole or clopidogrel also carry a class I

recommendation for ischemic stroke.21 Revascularization is generally recommended for patients with significant extracranial cerebral artery disease who have a stroke or transient ischemic attack, but the clinical benefit of revascularization is less well established for vertebral than for carotid arteries Carotid revascularization is contraindicated in patients with chronic total

occlusion, severe irreversible disability or poor life expectancy

Percutaneous Treatment of Carotid Artery Disease

Carotid endarterectomy (CEA) has long been established as the standard for

revascularization of both symptomatic and asymptomatic patients with significant carotid artery stenosis Contemporary trials of carotid artery stenting (CAS) using embolic protection devices have shown comparable results to CEA in selected patients.22-26 In CREST (Carotid

Revascularization Endarterectomy versus Stenting Trial) 2,502 patients with symptomatic or asymptomatic significant carotid stenosis were randomized to CAS or CEA.26Over four years of follow-up there was no difference in the composite primary endpoint of periprocedural stroke,

myocardial infarction, death or post-procedure ipsilateral stroke between CAS (7.2%) and CEA (6.8%, HR 1.11 [95% CI 0.81 to 1.51]) There was also no difference among subgroups of

symptomatic or asymptomatic patients Periprocedural death was similar between CAS and CEA groups (0.7% vs 0.3%, p=0.18), but periprocedural stroke was greater in the CAS group (0.1%

vs 2.3%, p=0.01) while myocardial infarction was higher in the CEA group (1.1% vs 2.3%, p=0.03) After 30 days postrevascularization ipsilateral stroke was similar between CAS and CEA groups (2% vs 2.4%, p=0.85) In the SAPPHIRE (Stenting and Angioplasty with

Protection in Patients at High Risk for Endarterectomy) trial, which enrolled 334 symptomatic (>50% carotid stenosis) and asymptomatic (>80% carotid stenosis) patients, the composite primary endpoint of death, stroke or myocardial infarction within 30 days postprocedure, death

or ipsilateral stroke 31 days to 3 years postprocedure were similar between groups with CAS at 24.6% and CEA at 26.9% (p=0.71) The rate of stroke was 9% in both CAS and CEA groups Current clinical guidelines recognize both CAS and CEA as options for revascularization, but weight their strengths of recommendation differently depending on patient characteristics (Table 2).21 In general, the selection of a revascularization method should be based on patient

comorbidities, the relative risks and benefits of both procedures, and understanding of patient preferences CAS when done by experienced interventionalists is the preferred method of

revascularization in patients with increased surgical risk (Fig 5) Table 3 shows factors that confer high risk for carotid endarterectomy Despite the results of published trials and clinical guidelines, current practice patterns for CAS in the U.S are strongly influenced by

reimbursement policies of the Centers for Medicaid and Medicare Services CAS is covered for stenosis ≥70% in symptomatic patients who have one or more high-risk features Asymptomatic patients with severe carotid stenosis may be covered for CAS only if performed as part of an approved trial or post-marketing study The influence of these reimbursement policies on referral for CEA and CAS has been shown in an analysis of 12,701 patients revascularized for carotid stenosis.27 This analysis found extreme clinical differences between patients treated with CEA and CAS with overwhelming burden of comorbidities and anatomical risk factors in the stenting group After adjusting for differences in patient characteristics, there was no difference in

mortality associated with CAS or CEA

Vertebral Artery Disease

Vertebral artery disease is usually discovered incidentally because it is rarely symptomatic Typically, symptoms of brainstem ischemia will not occur unless there is severe bilateral

vertebral stenosis The most common location for vertebral stenosis is at the ostium, which makes it particularly amenable to angioplasty and stenting with or without embolic protection There are no trials comparing percutaneous treatment with optimal medical treatment alone or surgery Coronary drug-eluting stents (DES) confer better long-term patency after vertebral artery stenting with a procedural success rate of 98-100% and five-year patency rate of >90%.28

Subclavian and Brachiocephalic Artery Disease

Occlusive disease of the subclavian and brachial arteries is underdiagnosed because patients are usually asymptomatic When symptoms occur, they take the form of subclavian steal

syndrome or upper extremity ischemia Subclavian steal occurs when there is proximal occlusion

of a subclavian artery causing reversal of flow from an ipsilateral vertebral artery into the upper extremity during exercise that can lead to symptoms of brainstem hypoperfusion If the internal mammary artery is used as a coronary bypass graft, myocardial ischemia can occur due to

subclavian-coronary steal Revascularization is not indicated in the absence of symptoms

Contemporary techniques for percutaneous revascularization (Fig 6) using nitinol,

self-expanding and bare-metal stents currently approved for iliac and femoral arteries provide a procedural success rate of 97-100%, <1% stroke and five-year primary and secondary patency rates of 83% and 96%, respectively.29,30

David R Holmes Jr This is an important group of patients In some patients post CABG who

have been treated with a LIMA to the LAD, there may be residual anterior wall ischemia as the result of severe subclavian stenosis Clinical measurement of bilateral arm pressures is an important screening test and should be performed in all patients either with symptoms, or in all patients with coronary artery disease

Renal Artery Disease

In a population-based screening study, the prevalence of significant renal artery stenosis detected by duplex ultrasonography was 6.8% in adults older than 65 years.31 Among patients undergoing angiography for coronary artery disease at our institution, the prevalence of renal artery stenosis >50% was 18%.32 Atherosclerosis is the cause of stenosis in 95% of patients with renal artery disease, but fibromuscular dysplasia is more common in young adult female patients who typically present with bilateral disease First-line management of renal artery disease

constitutes medical treatment for secondary prevention of atherosclerotic disease and

optimization of antihypertensive regimen In cases of significant renal artery stenosis with

recurrent, unexplained congestive heart failure or unexplained acute pulmonary edema

revascularization is a class I recommendation Revascularization for significant renal artery stenosis may be considered for patients with resistant or malignant hypertension, unstable angina

or chronic renal insufficiency in the presence of bilateral renal artery stenosis or stenosis to a solitary functioning kidney; however, the evidence for these indications remain controversial.9Renal artery surgery is seldom done, and renal artery stenting is the current method of

revascularization Balloon angioplasty alone is used for fibromuscular dysplasia, with stenting used only as bailout if there is dissection or suboptimal results However, for atherosclerotic renal artery stenosis, stenting is the treatment of choice when revascularization is indicated (Fig 7)

There has been a sharp decline in the use of renal stenting after the publication of recent negative randomized trials In a randomized trial of 140 patients with ostial atherosclerotic renal artery stenosis >50% and creatinine clearance <80 mL/min/1.73 m2, the primary endpoint of 20% decrease in creatinine clearance was similar between the stenting and medical therapy groups, 16% vs 22%, respectively, HR 0.73 (95% CI 0.33-1.61).33 However, this study was seriously underpowered to show efficacy, and 28% of patients assigned to stenting did not

receive a stent because stenosis on angiography was <50% In the ASTRAL (Angioplasty and Stenting for Renal Artery Lesions) trial 806 patients with renal artery stenosis >50% and

refractory hypertension or unexplained renal dysfunction were randomized to stenting plus medical therapy or medical therapy alone.34 The progression of renal dysfunction during a five-year period was slightly slower for the stenting group than medical therapy group, although there

was no difference in blood pressure, renal events and major cardiovascular events The major criticism of this trial was that patients who were expected to benefit from stenting were excluded, and only those with “uncertain” expected benefit were included This means that those patients with typical indications for renal revascularization by current guidelines were not included in the study.35 The most recent trial of renal stenting, CORAL (Cardiovascular Outcomes in Renal Atherosclerotic Lesions) randomized 947 patients to renal stenting plus medical therapy or medical therapy alone.36 In the initial design, patients were eligible for the trial if they had a systolic blood pressure >155 mmHg, were on at least two antihypertensive medications and had significant renal artery stenosis defined as ≥80% luminal diameter or 60-79% stenosis with ≥20 mmHg pressure gradient Due to slow enrollment, the eligibility was later expanded to include patients with glomerular filtration rate <60 mL/min/1.73m2 without a requirement for

hypertension After a median follow-up of 43 months, there was no difference in the composite primary endpoint of cardiovascular or renal events between the stenting plus medical therapy group (35.1%) and medical therapy alone group (35.8%, p=0.58) There was a small but

statistically significant and consistent decrease in mean systolic blood pressure in the stent group compared to the medical therapy group Ultimately, the current evidence does not justify renal stenting as routine treatment for renal artery stenosis in patients with renal dysfunction or

uncontrolled hypertension Until further evidence emerges, renal stenting should probably be limited to patients with unexplained recurrent congestive heart failure, as a last resort in patients with a single-functioning kidney or a bailout during invasive aortic procedures like endovascular aneurysm repair

Disease of the Celiac and Mesenteric Arteries

Disease of the celiac trunk, superior or inferior mesenteric arteries and their major branches typically occur in patients with atherosclerotic coronary or PAD Disease of these mesenteric arteries occurs in the form of atherosclerotic stenosis or thrombotic occlusion, but more rarely, aneurysms and fibromuscular dysplasia can occur Due to the extensive network of collaterals between these three major mesenteric arteries symptoms rarely develop unless two or all three arteries are diseased or acute occlusion before collaterals can be recruited Chronic mesenteric ischemia presents as postprandial pain, bloating and weight loss Alternatively, acute mesenteric ischemia is a life-threatening condition that can lead to bowel gangrene and perforation Acute

mesenteric ischemia is caused by acute thrombotic occlusion of a previously atherosclerotic artery, embolism (especially in atrial fibrillation), procedure-related occlusion or hypoperfusion

in patients with profound shock Catheter-based selective angiography is superior to duplex ultrasonography, computed tomography angiography and magnetic resonance angiography in establishing a diagnosis

Endovascular treatment with stenting has largely replaced surgical revascularization for mesenteric and celiac artery disease due to its lower morbidity and high technical success rate In the largest trial comparing surgical revascularization with angioplasty/stenting for celiac and mesenteric artery stenosis, surgical revascularization was associated with more serious

complications (36% vs 18%, p<0.001) and longer hospitalization (12 ±8 vs 3 ±5 days, p<0.001) than angioplasty or stenting treatment.37 However, at five-year follow-up, restenosis and

symptomatic recurrence was lower with surgical revascularization More recent studies of

mesenteric and celiac stenting have shown that concurrent treatment of two vessels during the index intervention decreases symptom recurrence and need for repeat interventions.38 Acute mesenteric ischemia still carries a high mortality rate, but a combined approach of endovascular revascularization plus laparotomy to explore and resect bowel infarction has been associated with lower mortality and morbidity than a totally surgical approach, 36% vs 50%, respectively, p<0.05.39 Endovascular treatment is particularly attractive in frail patients, those with multiple comorbidities or early postsurgical occlusion Hepatic artery stenosis and thrombosis is a major cause of graft loss after liver transplantation Percutaneous revascularization with angioplasty and stenting provides a good alternative to repeat surgery or repeat transplantation in these very sick patients.40 Endovascular revascularization with balloon angioplasty and stenting has become the procedure of choice for patients with post-transplantation hepatic artery stenosis and

occlusion at our center (Fig 8)

Lower Extremity Arterial Disease

Atherosclerotic lower extremity peripheral artery disease (LE-PAD) is the most

representative form of PVD Lower extremity peripheral artery disease affects about 1 in 6 people older than 65 years, but is underdiagnosed, and only 1 in 3 are treated.41,42 This is

unfortunate because LE-PAD is a major predictor of cardiovascular mortality and morbidity Most patients with LE-PAD are asymptomatic, but the diagnosis can be made easily with an

ankle-brachial index of ≤0.9 It is a class I recommendation to screen asymptomatic patients who are 65 years or older, ≥50 years old with history of smoking or diabetes mellitus, or have

abnormal pulse on exam.43 All patients with LE-PAD need a comprehensive cardiovascular risk assessment The goals of therapy should be to prevent cardiovascular mortality and morbidity, relieve symptoms and preserve the limb Antiplatelet treatment with aspirin, high-potency statin therapy, smoking cessation, control of diabetes and hypertension are the corner stones of medical therapy Among the antihypertensive medications, beta blockers and angiotensin-converting enzyme inhibitors should be first-line agents because they can reduce myocardial infarction, stroke and cardiovascular mortality in patients with PAD.44,45 Cilostazol is effective in reducing claudication pain and improving walking distance in patients with LE-PAD.46 Adherence to a walking program promotes the growth of collaterals, improves endothelial function and muscle metabolism Several trials have demonstrated that a supervised exercise program increases waking distance, but the benefit of unsupervised programs is uncertain.47 A modified, home-based exercise program using a step counter or pedometer to quantify activity may provide similar adherence rates and improvement in claudication as a facility-based supervised exercise program.48,49 Interventional cardiologists are in a unique position to manage and coordinate these noninvasive aspects of treatment for LE-PAD, and provide the option of percutaneous

revascularization when indicated Based on clinical presentation, LE-PAD is divided into three different entities: stable disease with intermittent claudication, chronic critical limb ischemia or acute limb ischemia The Rutherford classification is used to stage the clinical severity of lower extremity ischemia (Table 4) Revascularization is indicated for stable LE-PAD with

claudication only when symptoms are refractory to optimal medical therapy and interfere with usual lifestyle or vocational activities On the other hand, revascularization is indicated as initial treatment for critical limb ischemia (rest pain, non-healing ulcer or gangrene) and acute limb ischemia

David R Holmes Jr This area has received increasing attention from Cardiovascular Societies

because of the prevalence of the disease, its underappreciated significance and the potential for morbidity and mortality Patients with advanced disease discussed below need a focused

approach with involvement of Vascular Surgeons, Vascular Medicine Specialists, Interventional Cardiologists and Radiologists, Wound care specialists and often Orthopedic surgeons (this latter group particularly in very end stage disease patients.)

Revascularization for Critical Limb Ischemia

Critical limb ischemia is chronic underperfusion of the extremity manifesting as rest pain, non-healing ulcer or gangrene (i.e., Rutherford class 4, 5 and 6) Critical limb ischemia carries a dismal prognosis with one-year mortality >20% and 6-month amputation rate without

revascularization of about 40%.50 Patients with critical limb ischemia commonly have

multisegment disease in series (e.g., iliac, femoropopliteal, below-knee) or in parallel (like

coexisting superficial femoral and deep femoral, or simultaneous involvement of ≥2 below-knee vessels) There is no effective medical therapy for critical limb ischemia, and revascularization is required to establish in-line uninterrupted flow to the foot Some early phase II and III trials have tested biological treatments like angiogenic growth factors and stem cells in patients with critical limb ischemia, but the findings are preliminary and inconclusive.51-53

Patients with critical limb ischemia often have multiple comorbidities like diabetes mellitus, renal insufficiency, coronary disease, frailty and other systemic diseases These comorbidities increase the risk of open surgical revascularization for this critically ill population In patients who have poor outflow below the knee, surgical revascularization for femoropopliteal disease is usually not a good option because of the risk of graft thrombosis Advances in the devices and techniques for percutaneous intervention have made percutaneous transluminal angioplasty the preferred treatment option whenever feasible (Figs 9 and 10) With current equipment, the

success rate with percutaneous treatment is high, even in long occlusions In the Bypass vs Angioplasty In Severe Ischemia of the Leg (BASIL) trial, 452 patients with critical limb

ischemia and infrainguinal disease were randomized to surgical bypass versus balloon

angioplasty.54 There was no difference in amputation-free survival at three years between

angioplasty (52%) and surgical revascularization (57%, HR 0.89 [95% CI 0.68 to 1.17])

We manage patients with critical limb ischemia in a comprehensive program comprised of interventional cardiology, vascular surgery, hyperbaric medicine/wound care and infectious disease specialists In patients with complex inflow and outflow disease a staged approach that combines percutaneous and surgical revascularization may be undertaken

Endovascular Treatment of Acute Limb Ischemia

Acute limb ischemia is a real medical emergency that requires urgent revascularization It is

a rapidly evolving or sudden decrease in limb perfusion that threatens limb viability Acute limb ischemia typically results from embolization or local thrombus formation in a previously

diseased arterial segment Prompt administration of aspirin and parenteral anticoagulation should

be started If the limb is salvageable, emergent imaging should be done to identify the level of occlusion and direct prompt revascularization Traditional teaching had stipulated that patients with stage IIa (marginally threatened) acute limb ischemia for which there is no or minimal sensory loss should preferably undergo endovascular treatment, while stage IIb (immediately threatened) should preferably be managed surgically.55 The method that provides the fastest reperfusion should be used, and this will depend on the local realities at every institution

Catheter-directed thrombolysis (CDT) with or without mechanical thrombectomy can provide prompt and safe restoration of limb perfusion in both stage IIa and IIb acute limb ischemia (Fig 11)

Percutaneous treatment with intra-arterial CDT is the treatment of choice for acute limb ischemia lasting <14 days.9 After 14 days the clot gets organized and thrombolysis becomes less effective In the Surgery Versus Thrombolysis for Ischemia of the Lower Extremity (STILE) trial, 393 patients with acute limb ischemia due to occlusion of native arteries or bypass grafts were randomized to surgical revascularization or intra-arterial CDT with tissue plasminogen activator or urokinase.56 Among patients who presented within 14 days of symptom onset the 30-day composite primary endpoint of adverse clinical events was similar between the thrombolysis group (61.4%) and surgical group (53.8%, p=0.46) However, beyond 14 days of symptom onset the primary endpoint occurred more commonly in the CDT group (62.9%) than surgical group (29.2%, p<0.001) In the Thrombolysis or Peripheral Arterial Surgery (TOPAS) trial, 544

patients with acute limb ischemia within 14 days of symptom onset were randomized to arterial CDT with recombinant urokinase or surgical revasculariztion.57 At six months there was

intra-no difference in the primary endpoint of amputation-free survival between CDT (71.8%) and surgical revascularization (74.8%, p=0.43) The incidence of nonfatal bleeding complications was higher in the thrombolysis group, while the need for subsequent open surgical procedures was higher in the surgical revascularization group

In patients with high clot burden CDT can be combined with mechanical thrombectomy After clot dissolution, residual lesions are managed by angioplasty with or without stenting After revascularization, close monitoring is required for reperfusion injury, which can lead to life-threatening metabolic, renal, pulmonary and cardiac dysfunction

David R Holmes Jr By virtue of knowledge and experience with lytic therapy as well as

mechanical thrombectomy devices which have been widely used in the coronary arena,

interventional cardiologists have an important role in the treatment of these patients Obviously they need to be expertly trained, have ongoing experience in the field and be familiar with all aspects of the patient care

Endovascular Treatment of Suprainguinal Disease

Suprainguinal LE-PAD refers to the vascular territory involving the external iliac and

common iliac arteries into the distal abdominal aorta Guidelines for PAD recommend that percutaneous revascularization should be preferred over surgery when the lesion anatomy

suggests a high likelihood of technical success and long-term patency or in patients who are high risk for surgery.9 The Trans-Atlantic Inter-Society Concensus (TASC) II classification is used to denote the extent of LE-PAD (Fig 12), and serves as a basic guide to the method of

revascularization Percutaneous angioplasty and stenting is the treatment of choice for focal aortoiliac disease (TASC type A and B) Stenting for such iliac lesions has a procedural success rate >95% with five-year primary patency rates of about 80%, similar to surgery but with much lower morbidity.58,59 At the common femoral artery endarterectomy is the criterion standard for revascularization Surgical revascularization is the treatment of choice for TASC type C and D lesions; however, with advances in stent design, contemporary studies of type C and D iliac lesions have shown a good three-year primary patency rate of 76% and secondary patency of 90%.60 Traditional teaching was to perform balloon angioplasty and stenting reserved only for cases with suboptimal angioplasty results A meta-analysis of 14 trials including 2,116 patients compared the practice of balloon angioplasty with selective provisional stenting versus primary stenting The procedural success with primary stenting was 96% compared to 91% with balloon angioplasty, and the risk of long-term failure was 39% lower with primary stenting compared to balloon angioplasty.61 The current standard of care for iliac endovascular intervention is stenting with or without balloon pre- and postdilatation In patients with bilateral iliac disease, we

advocate the “kissing technique” with 100% procedural success and a two-year primary patency rate of about 90% (Fig 13).62

Endovascular Treatment of Femoropopliteal Disease

The superficial femoral and popliteal arteries are the most common sites of symptomatic PAD, and are the most common targets of PAD revascularization procedures The TASC II classification provides a clinical guide for describing the complexity of femoropopliteal lesions (Fig 12) Long, chronic occlusions in TASC type D are best treated by bypass surgery if the patient is a good surgical candidate and there are good venous conduits available Endovascular intervention is the treatment of choice for TASC type A and B femoropopliteal lesions (Fig 14) With the availability of more advanced devices, TASC type C lesions are increasingly being successfully treated endovascularly The traditional standard of endovascular revascularization for femoropopliteal disease has been balloon angioplasty The long-term patency of stents in the femoropopliteal location is limited, not only by the hemodynamic characteristics of the lesions and distal runoffs, but also the mechanical forces to which the artery is subjected Forces of torsion, stretching and bending can all lead to deformation and fracture of the stent, which

LE-manifests as restenosis and occlusion This was more common with older cobalt-based or based stents.63,64 Conventional teachings dictate primary balloon angioplasty and provisional stenting only as “bailout” if there is >50% residual stenosis, residual pressure gradient >10 mmHg or a flow-limiting dissection However, more recent data shows better long-term patency with primary stenting using contemporary nitinol self-expanding stents compared to balloon angioplasty Nitinol self-expanding stents provide more flexibility while maintaining a small delivery profile and good radial strength The most impressive demonstration of this is in a registry using the Supera stent (Abbott, Abbott Park, Illinois) in popliteal lesions (40 to 240 mm) with 12-month primary patency of 87.7% and no stent fractures at mean follow-up of 15

steel-months.65

Modern self-expanding nitinol stents have shown higher long-term patency rates than balloon angioplasty in several trials Generalizations are difficult to make because long-term patency depends on lesion characteristics like length, calcification, chronicity and quality of inflow and outflow vessels Of these lesions, length seems to have the most negative effect on patency The 1-year patency for femoropopliteal stenting is in the range of 70-80%, compared to about 30-

50% for balloon angioplasty alone.66-69 However, the patency rates fall sharply for lesions longer than 150 mm Second generation nitinol self-expanding stents have improved radial strength and flexibility and come in lengths up to 200 mm Recent studies including patients with

femoropopliteal lesions longer than 200 mm treated with such stents report 12-month primary patency rates of 68-80% and secondary patency rates of 89-93%.70,71

One solution proposed to remedy the high restenosis rates after endovascular treatment in long femoropopliteal lesions was the Gore® Viabahn® polytetrafluoroethylene (PTFE)-covered nitinol self-expending stent (Newark, DE), which creates a graft that can be delivered

percutaneously through a low profile system There was great enthusiasm in early studies that compared the Viabahn stent to femoropopliteal bypass surgery using Dacron or PTFE grafts in patients with mean lesion length 256 mm.72 The 12-month primary patency rates were similar between Viabahn (73.5%) and bypass surgery (74.2%), and no difference in repeat

revascularizations In lesions <130 mm in length, the 12-month primary patency was 95%.73 The most common reason for failure in Viabahn stents was edge thrombosis Unfortunately, the addition of heparin bonding to the PTFE covering has not prevented this problem However, such cases of edge thrombosis or restenosis can be effectively treated with CDT and balloon angioplasty One application for which the utility of covered stents like the Viabahn has been outstanding is for the treatment of aneurysms and perforations (Fig 15) In such cases, the

endoprosthesis can effectively reline the inner wall of the artery isolating the diseases segment

David R Holmes Jr Treatment of disease in the aorto-iliac vessels is an essential part of the

training for structural heart disease interventional cardiologists The catheters used for the

treatment of aortic and mitral valve pathology are large and vascular complications have been a significant problem According the need for a variety of devices including covered stents is essential

New Drug-Eluting Technologies for Femoropopliteal Disease

Despite the success of self-expanding nitinol stents, long-term restenosis remains a major limitation of endovascular intervention in femoropopliteal disease The success of drug-eluting stents in decreasing restenosis and target lesion revascularization in coronary arteries has

triggered a lot of interest in applying a similar principle to PAD In the Zilver PTX trial, a

strategy of primary stenting with a paclitaxel-eluting nitinol stent was compared with the

standard revascularization strategy of balloon angioplasty and provisional stenting in 474

patients with femoropopliteal disease (mean length 65 mm).74 Patients in the balloon angioplasty group who had suboptimal angioplasty were further randomized to the paclitaxel-eluting nitinol stent or conventional bare nitinol stent At 12 months, the primary patency was significantly higher in the paclitaxel-eluting stent group (83.1%) than in the balloon angioplasty group

(32.8%, p<0.001) The rate of freedom from major adverse events (death, amputation, target lesion revascularization, target limb ischemia requiring surgery or Rutherford class 5/6 ischemia) was also higher in the paclitaxel-eluting stent group (90.4%) than in the balloon angioplasty group (82.4%, p=0.004) In a registry of 787 patients with 900 femoropopliteal lesions averaging

99 mm that were treated with the Zilver PTX stent, 12-month primary patency was 86.2% and freedom from target lesion revascularization 90.5%, while the stent fracture rate was 1.5% 75There is great interest in the use of stentless revascularization methods for femoropopliteal disease due to the mechanical forces to which these arteries are subjected The addition of

antiproliferative pharmacotherapy to angioplasty balloons is thought to decrease long-term restenosis while avoiding the inherent problems related to stenting Drug-coated balloons (DCB) have gained popularity in Europe where they are approved, but remain investigational in the U.S Multiple small studies have shown that paclitaxel DCB reduce restenosis and target lesion

revascularization in the first year compared to conventional balloon angioplasty, but no term results are available.76-78 In a meta-analysis of such trials comparing DCB with

long-conventional balloon angioplasty in femoropopliteal lesions, the six-month rate of restenosis and target lesion revascularization was significantly lower with DCB (18.7% and 12.2%,

respectively) than with conventional balloon angioplasty (45.5% and 27.7%, respectively,

p<0.001).79 The main advantage of DCB may be in popliteal, common femoral and ostial

superficial femoral lesions where it is important to avoid stenting because of joint flexion and the need to preserve future options for femoropopliteal bypass Drug-coated balloons are expected to become the treatment of choice for in-stent restenosis In a recent series of patients with in-stent restenosis of the superficial femoral artery treated with a paclitaxel DCB, the 12-month primary patency was 92.1% and all patients had improved claudication and ankle-brachial index at 12 months.80

Endovascular Treatment of Infrapopliteal Disease

David R Holmes Jr This is an area that continues to be associated with suboptimal longer term

outcomes As the authors document, long term patency is far from ideal New technology such

as drug eluting balloons and bioabsorbable vascular scaffolds hold promise

There are no studies that show the effectiveness of revascularization of tibial and peroneal artery disease for intermittent claudication However, it may be acceptable to perform

angioplasty for below-knee disease during endovascular treatment for femoropopliteal disease in patients with claudication Revascularization for infrapopliteal disease is indicated for limb salvage intervention in patients with critical limb ischemia (Fig 9) Below-knee disease is

typically diffuse, making the long-term success of revascularization difficult The 12-month patency of femorotibial grafts is 48-60%, but when below-knee runoff is poor the 12-month patency is only 20%.81 Due to the suboptimal results from surgery, endovascular

revascularization is usually the go-to option for infrapopliteal disease when feasible Angioplasty using current low-profile balloons is associated with more than 90% technical success rate Even cases with diffuse disease can be treated with long balloons up to 20 cm in length; however, 12-month restenosis rates are as high as 50%.82 This is still acceptable given that the goal is to provide in-line flow to the foot to promote healing of ulcers or gangrene The useful endpoint for such interventions is limb salvage rather than restenosis Stenting may be used for infrapopliteal disease when there is significant residual stenosis or flow-limiting dissection from balloon

angioplasty Both bare-metal stents and DES have been used, but the long-term patency and wound healing is better with DES.83,84 There is ongoing research on bioabsorbable stents for infrapopliteal disease, but findings are still very preliminary

The most promising new technology for endovascular treatment of infrapopliteal disease is the DCB In the Drug-Eluting Balloon for Below The Knee Angioplasty Evaluation (DEBATE BTK) trial, 132 diabetic patients with 158 infrapopliteal lesions averaging about 130 mm in length presenting with critical limb ischemia were randomized to DCB or standard balloon angioplasty.85 The one-year primary patency rate was 73% for DCB and 26% for standard

angioplasty (p<0.001), while the symptom-driven target lesion revascularization was lower with DCB (18%) than standard balloon angioplasty (43%, p=0,002) In the Drug-Eluting Balloon Evaluation for Lower Limb Multilevel Treatment (DEBELLUM) trial, 50 patients with 122

femoropopliteal and infrapopliteal lesions were randomized to paclitaxel DCB or standard

balloon angioplasty.86 The six-month binary restenosis rates were 9.1% in DCB versus 28.9% in standard angioplasty (p=0.03), and the target lesion revascularization rates were 6.1% versus 23.6%, respectively (p=0.02) Ankle-brachial index and clinical Fontaine stage also were better

in the DCB group Larger studies are ongoing to evaluate DCB in North America, but they have already been approved for clinical use in Europe

Adjuvant Therapies for Calcified Lesions and Chronic Total Occlusions

Adjuvant therapies like atherectomy, cutting balloon angioplasty, re-entry devices and laser and brachytherapy may be useful to increase the technical success of endovascular intervention

of difficult lesions, but their effectiveness is not well established They are reserved for select cases as a bailout when standard angioplasty is unsuccessful Atherectomy is useful to debulk chronic occlusions and heavily calcified lesions Several atherectomy systems are commercially available; they consist of a flexible, low-profile catheter with some form of cutting device at its distal tip that progressively abrades the plaque, creating a channel so angioplasty can be

performed (Fig 10) Using atherectomy devices, the procedural success rate in these difficult interventions is more than 90%, but they have not been shown to reduce the need for bailout stenting or improve long-term patency compared to standard angioplasty.87,88

The retrograde approach has become a popular option in chronic occlusions that cannot be crossed in the standard antegrade fashion In a multicenter registry of 130 patients with

superficial femoral artery occlusions, the popliteal retrograde approach was employed as a

bailout when the standard antegrade approach from the common femoral artery was

unsuccessful.89 The procedural success increased from 86% with the standard antegrade

approach to 95.7% using the bailout retrograde popliteal approach without any increase in

procedural complications

Percutaneous Treatments for Venous Occlusive Disease

Mortality associated with venous thromboembolic disease has been long recognized, but the morbidity associated with venous disease has long been overlooked Venous disease usually comes to the attention of a vascular expert in the form of acute occlusion like deep vein

thrombosis (DVT) with or without embolism, chronic post-thrombotic syndrome, extrinsic

compression of central veins or lower extremity venous insufficiency The typical symptoms include engorgement, edema and pain distal to the anatomical obstruction In cases of chronic venous insufficiency of the lower extremities debilitating ulcers can develop Interventional cardiologists have applied similar principles used in arterial disease to endovascular treatment of venous occlusive disease

David R Holmes Jr This area has not been typically the purview of interventional

cardiologists It does represent major challenges, but major opportunities both for training

programs as well as for practicing physicians The patient population is large and the potential for morbidity is great

Deep Venous Thrombosis of Lower Extremities

The annual incidence of DVT among community-dwelling adults is about 2-7 per 10,000.90This rate is 100 times greater among hospitalized patients and of whom 20% will have a

recurrent thromboembolic event within five years.91,92 Patients with distal DVTs may be

asymptomatic and have little sequelae, but proximal or iliofemoral DVTs carry significant

morbidity and are more likely to embolize, causing potentially fatal pulmonary embolism

Because proximal DVTs occlude the venous outflow from the entire limb, they have a high risk

of causing post-thrombotic syndrome (PTS) Although pulmonary embolism is the most feared complication, PTS is associated with significant long-term morbidity and health care costs Post-thrombotic syndrome manifests as chronic pain, swelling and venous insufficiency affecting 33-87% of patients with lower extremity DVT.93,94 Post-thrombotic syndrome in its most severe form presents as phlegmasia cerulea dolens when thrombosis obstructs major and collateral veins, resulting in venous congestions with massive fluid sequestration and edema, severe pain and cyanosis evolving into skin and subcutaneous tissue gangrene if untreated Anticoagulation needs to be initiated promptly for DVT to prevent clot expansion and propagation, but because it does not get rid of the clot that is already present, PTS can still develop, hence justifying the need for thrombus removal.95 Early efforts at clot removal in patients with extensive iliofemoral DVT were done through surgical thrombectomy with varying success.96,97 However, due to the morbidities of this surgery, it has been replaced by contemporary endovascular techniques, namely CDT and mechanical thrombectomy

Catheter-directed Thrombolysis

The rational for CDT is to deliver appropriate amounts of fibrinolytic medication directly into the clot where it is needed while decreasing the systemic effects of thrombolysis This is achieved by obtaining venous access from the contralateral femoral, ipsilateral popliteal and internal jugular veins, and advancing a catheter to obtain angiograms to identify the level of occlusion.98 An infusion catheter is then advanced over a guidewire into the thrombus, and continuous slow infusion of the thrombolytic agent is directed into the clot over 24 to 48 hours Concomitant heparin also is given via a peripheral vein with monitoring of clotting time and fibrinogen Follow-up venography is repeated after the infusion to assess patency of the vein and plan further interventions like angioplasty or stenting for residual fixed lesions CDT for

iliofemoral DVT carries a procedural success rate of about 80-85% in achieving complete

recanalization of the supra and infrainguinal venous drainage.99-102 Major bleeding occurred in 10% of patients, with less than 1% of intracranial bleeding and <0.5% mortality There has been concerns of pulmonary embolism related to dislocation of the clot as it undergoes lysis, leading some experts to propose prophylactic placement of retrievable inferior vena cava (IVC) filters before CDT; however, the rate of pulmonary embolism in these reports was <1% In the largest

5-of such series from the National Venous Registry by Mewissen et al., based on 312 limbs with massive lower extremity DVT limb, patency was achieved in 75% with CDT using urokinase, and one-year primary patency was 60%.100 In this registry, 34% needed iliac vein angioplasty or stenting for residual lesions Urokinase, alteplase and reteplase all have been used in studies of CDT for DVT The relative effectiveness of these three drugs were compared in a study by Grunwald et al.103 The procedural success was similar with the three drugs at 97-100%, with slightly shorter infusion times for alteplase (30 hours) and retaplase (24.3 hours) compared to urokinase (40.6 hours) The cost of the medication was much less with alteplase $488 than with reteplae $1,787 or urokinase $6,577 (p<0.01)

Until recently there has not been any randomized-controlled trial of CDT The directed Venous Thrombolysis (CaVenT) trial compared CDT using alteplase in addition to conventional therapy versus conventional anticoagulation therapy alone in 209 patients with acute iliofemoral DVT within 21 days of symptom onset who were at low to moderate risk of bleeding.104 At 24-month follow-up, the rate of symptomatic PTS was lower in the CDT group (41.1%) than the conventional therapy group (55.6%, p 0.047) Iliofemoral vein patency at six

Catheter-months was higher in the CDT group than in the conventional therapy group (65.9% vs 47.4%, p=0.012) The major bleeding rate related to CDT was 3.3% while there was no major bleeding

in the conventional therapy group There was no death, pulmonary embolism or intracranial bleed in the CDT group Despite the positive outcome of this trial, it has been criticized for its low use of angioplasty/stenting to treat residual venous lesions; which could account for the lower than expected vein patency after CDT Other studies have reported underlying stenotic venous lesions in 80% of patients with iliofemoral DVT that can be successfully treated with angioplasty or stenting.105,106

Pharmacomechanical Thrombolysis

Percutaneous mechanical thrombectomy using a variety of commercially available devices has been used in patients with extensive proximal DVT In contemporary practice the standard of care has evolved to combining CDT in which the fibrinolytic agent is delivered as a pulse-spray with adjunctive mechanical thrombolysis This strategy has been termed pharmacomechanical thrombolysis, which can lead to faster thrombus resolution, increased vein patency and decreased distal emboli than CDT alone.107,108 The outcomes of pharmacomechanical thrombolysis have been evaluated in a systematic review including 16 nonrandomized studies and 481 patients.109Technical success was achieved in 83-100% of patients with a 7.5% rate of bleeding

complications, <1% incidence of symptomatic pulmonary embolism and no deaths or strokes Freedom from PTS symptoms was 75-98% at six- to 24-month follow-up in these studies

Catheter-directed thrombolysis was compared to pharmacomechanical thrombectomy with the Angiojt catheter (Possis Medical, Minneapolis, MN) in 93 patients.110 Both the CDT and

pharmacomechanical thrombectomy groups had similar rates of complete thrombus removal and symptom improvement (70% vs 75% and 78 vs 82%, respectively) However, patients in the pharmacomechanical group had fewer repeat venograms (0.4 vs 2.5), shorter intensive care unit stays (0.6 vs 4.6 days) and hospital stays (2.4 vs 8.4 days) than the CDT group, leading to significant reduction in cost These early experiences suggest that pharmacomechanical

thrombolysis is a superior strategy for thrombus removal than CDT; however, more controlled studies are needed

May-Thurner Syndrome

May-Thurner syndrome presents as extensive DVT of the left lower extremity due to

compression of the left common iliac vein by an overriding right common iliac artery It should

be suspected in left iliofemoral DVT in young patients without clear risk factors of DVT

Endovascular treatment is done by CDT and stenting of the compressed iliac vein In a published series of patients with May-Thurner syndrome treated by CDT, repeat occlusion occurred in only 5% of patients who had stenting of the common iliac vein, while all patients who had only

balloon dilatation experienced reocclusion.111

Inferior Vena Cava Filters

Deep vein thrombosis occurs in 422 out of 100,000 people per year, and if untreated will cause pulmonary embolism in 40% of patients.112,113 Anticoagulation is the well-established first-line treatment for venous thromboembolic disease, but the rate of recurrent thrombotic events is 0.6 to 1.5 per 100 patient-years and the rate of major bleeding while on anticoagulation is 0.9 to 4.6 per 100 patient-years.114 Since their introduction in the 1970s, IVC filters have been used to prevent pulmonary embolism in high-risk patients The technical ease and safety of IVC filter placement have significantly improved over the years, which was associated with a sharp

increase in the use of IVC filters in the U.S between 1990 and 2004.115 There has been

significant controversy about which patients benefit from IVC filter placement, a situation that has not been helped by the lack of synchrony between guidelines from different professional societies (Table 5).116-119 There is however a strong general consensus to recommend IVC filters

in patients with venous thromboembolic disease who have a contraindication to anticoagulation There are multiple case series reporting the outcomes of treatment with IVC filter, but there

is a surprising paucity of good controlled trials In a population-based study of hospital

admissions for venous thromboembolic disease in California, 3,632 patients treated with an IVC filter plus routine treatment were compared with 64,333 controls who received routine treatment alone.120 There was no difference in recurrent admission for pulmonary embolism between patients treated with IVC filters and controls; however, incidence of recurrent DVT was higher

in the filter group The only randomized controlled trial on IVC filters was the PREPIC

(Prévention du Risque d'Embolie Pulmonaire par Interruption Cave) trial in which 400 patients

with proximal lower extremity DVT were randomized to receive a permanent IVC filter plus anticoagulation or anticoagulation alone.121 At day 12 the incidence of pulmonary embolism was lower in the filter group (1.1%) than in the anticoagulation group (4.8%, OR 0.22 [95% CI 0.05-0.90)]; and after 2 years the rates of pulmonary embolism were 3.4% in filter group and 6.3% for anticoagulation alone However, the rate of recurrent DVT after 2 years was higher in filter group (20.8%) than in the anticoagulation group (11.6%) The benefit of IVC filers is expected to

be higher in unstable patients with pulmonary embolism This was demonstrated in a study of 38,000 patients with unstable pulmonary embolism where the mortality was 33% in patients treated with IVC filter versus 51% in those who did not receive an IVC filter (p<0.001).122 When the decision to place an IVC filter has been made, the operator needs to choose

between a permanent or retrievable filter Due to the increased risk of recurrent DVT with filters,

it is recommended that a retrievable filter be used in patients for whom the condition that

justifies placing the filter is reversible The filter should be retrieved when the risk of pulmonary embolism is decreased since the failure rate of retrieval increases with time due to scarring around the filter

David R Holmes Jr As has been true with other vascular territories, in the past, vascular

radiologists have played the major role in treatment Certainly interventional cardiologists can become expert in these settings, but typically that has not been the case except in individual institutions where care patterns may be uniquely different

Veno-Occlusive Disease of Upper Extremities

About 10% of all DVTs affect the upper extremities but this proportion is increasing due to the use of long-term central venous catheters.123 Upper extremity DVT can be classified as proximal (affecting axillary and subclavian veins) or distal (brachial and radial/ulnar veins) The DVT also can be described as primary when there is no underlying venous disease or secondary when associated with central venous instrumentation or other obstructive pathology The most common form of primary upper extremity DVT occurs in people with underlying venous

thoracic outlet syndrome The typical example of this is Paget-Schroetter syndrome, which occurs in young healthy people, mostly men, after vigorous upper extremity exercises with repetitive raising of the arms.124 When upper extremity DVT extends proximally into the

innominate vein it can lead to superior vena cava (SVC) syndrome The most common form of

SVC syndrome occurs from tumor infiltration or extrinsic compression of the SVC in patients with lung cancer, non-Hodgkin lymphoma, thymoma or other upper mediastinal processes Upper extremity DVT causes fewer complications than lower extremity DVT In patients with upper extremity DVT, the risk of pulmonary embolism is 2-9% (compared to about 25% in lower extremity DVT), PTS occurs in 7-47% and mortality is about 11%.125,126 The goals of treatment are to prevent pulmonary embolism, recurrence and PTS Therapeutic anticoagulation

is the foundation of all treatment for upper extremity DVT Most catheter-related DVTs are small and can be managed conservatively However, if there is large occlusive proximal DVT related to a catheter, the catheter should be removed, if possible, after anticoagulation is initiated, and preferably replaced from the contralateral side after a catheter-free interval period

Endovascular intervention with CDT, pharmacomechanical thrombolysis, balloon angioplasty, stenting or a combination of these options is the treatment of choice in cases of SVC syndrome, Paget-Schroetter syndrome or other cases of venous thoracic outlet obstruction when symptoms are severe and bleeding risk is low to moderate (Fig 16).127 In cases of Paget-Schroetter

syndrome, surgical thrombectomy followed by excision of the first rib to widen the thoracic outlet has for long been the definitive treatment However, contemporary practice leans more in favor of endovascular approaches Despite the lack of randomized trials, extrapolations have been drawn from the experience with lower extremity DVT In a systematic review of 47

published studies involving 2557 patients with upper extremity DVT, endovascular treatment with CDT or mechanical thrombectomy was used in 38% of patients achieving vein patency in 90% of patients and freedom from PTS symptoms in 83% of patients.128 SVC filters have also been proposed to prevent pulmonary embolism in patients with upper extremity DVT, but their use remains off label at the present time

Renal Denervation Therapy for Resistant Hypertension

Resistant hypertension refers to persistent elevation of systemic blood pressure >160/100 mmHg on at least three antihypertensive medications at maximally tolerated doses one of which

is a diuretic. 129 This excludes secondary hypertension like renovascular disease, chronic kidney disease, endocrine disease or obstructive sleep apnea Depending on the population studied the prevalence of resistant hypertension ranges from 10 to 20% of all patients treated for

hypertension and confers a higher risk of cardiovascular mortality and morbidity. 130, 131 Such patients have been shown to have increased sympathetic activity from the renal afferent network, and the sympathetic activity is proportional to the elevation in blood pressure. 132 Historically surgical sympathectomy had been used to treat severe hypertension with improvement in blood pressure control and survival compared to conventional therapy at the time. 133 However this therapy was abandoned due to high surgical operative mortality and morbidity The use of a catheter inserted percutaneously into the renal artery to ablate the renal sympathetic network has been proposed as a minimally invasive and safe treatment for resistant hypertension After

engaging the renal artery with a guiding catheter, a radiofrequency ablation catheter is inserted into the renal artery and energy is delivered into the arterial wall to destroy adventitial nerves Early trials stimulated great enthusiasm for renal sympathetic denervation (RSDN) in

patients with resistant hypertension In the Simplicity phase 1 and 2 trials RSDN produced a decrease in office measured systolic blood pressures of 25 to 32mmHg that was observed up to 2 years. 134-136 There were no serious complications; vascular complication rate was about 1% However in the Simplicity phase 2 trial no decrease in adverse cardiovascular events, strokes or renal failure was observed from RSDN compared to medical therapy The Symplicity HTN-3 trial went a step further to address several drawbacks of the previous trials This was a single-blind trial patients with resistant hypertension were randomized to RSDN (364 patients) or to a sham procedure (171 patients) at 88 sites in the United States. 137 Both groups received optimal medical therapy At 6 months both the RSDN group and sham procedure group had significant reductions in systolic blood pressure from baseline; -14.13±23.93 mmHg and -11.74±25.94 mmHg respectively, both p<0.001 However there was no difference in office blood pressure reduction between RSDN and sham procedure groups -2.39 mmHg (95% CI -6.89 to 2.12,

p=0.26) The change from baseline in 24-hour ambulatory blood pressure was modest and also similar between RSDN (-6.75±15.11 mmHg) and sham procedure (-4.79±17.25 mmHg), for a difference of -1.96 mmHg (95% CI -4.97 to 1.06, p=0.98) There was no difference in primary safety endpoints between the two groups

Catheter-based RSDN for resistant hypertension is currently approved for clinical use in Europe A recently published study of RSDN at 10 European centers showed lower than

expected but significant reductions in blood pressure. 138 The mean office systolic blood pressure

at baseline was 174.5±25.7 mmHg and the mean 24-hour ambulatory systolic pressure at

baseline was 156.7±17.4 mmHg At 6 months after RSDN there was a mean decrease in office systolic blood pressure of -17.6mmHg (95% CI -22 to -13.1) and decrease in 24-hour ambulatory pressure of only -5.9mmHg (95% CI -9 to -2.8) The wide confidence intervals and large

standard deviations in these results point to the variability of response to RSDN It highlights the need for further study and risk stratification to identify patients that are most likely to benefit from this therapy The starting point needs to be the identification of patients whose hypertension

is truly resistant to aggressive medical therapy Analysis of data from 11 European hypertension referral centers shows that of 731 patients that were referred to RSDN, 46.9% had blood pressure normalized after adjustment of medications and 11.1% had secondary causes of hypertension. 139One major drawback of the Simplicity trials so far has been that there was no method used to verify adequate sympathetic denervation Newer systems with multipolar electrodes may be able

to deliver more reliable destruction of the renal sympathetic bed but they still remain to be tested

in randomized trials. 140,141 Nonetheless, the future of RSDN at this time appears uncertain

Conclusion

The past decade has been a period of significant expansion of the interventional

cardiologist’s scope of practice Significant innovations in the devices used for the treatment of a wide range of vascular diseases have opened new opportunities for less invasive endovascular treatments The training and skill set of interventional cardiologists have also evolved to meet the challenges of today’s patients who tend to have more complex pathology, more comorbidities as well as a higher expectation for safe and effective treatments with little associated morbidity These advances in the technology and techniques of endovascular treatment for PVD provide the interventional cardiologist an opportunity to manage patients as a complete cardiovascular

expert Interventional cardiologists are trained and experienced in the principles and techniques

of intervention on both large and small vessels A lot of the principles of coronary intervention have been adapted to intervention on larger vessels Safe and appropriate vascular access is the first step In today’s practice the interventional cardiologist has the skill set to secure

percutaneous access from different sites including, but not limited to, radial, brachial, subclavian, femoral, popliteal or tibial arteries Working with surgeons on complex hybrid procedures, access can be obtained directly through the iliac artery, aorta or even left ventricular apex for endovascular repair of aortic aneurysms using large devices After the intervention there are

several options for closing the vascular entry site using traditional external compression or a variety of small and large vessel closure devices to achieve hemostasis Surgical management of the vascular access site is required when sheaths larger than 20-24 Fr are used The trend in today’s practice is for closer collaboration between interventional cardiologists and vascular surgeons to co-manage patients and perform hybrid procedures for complex cases We use a formal “Vascular Team” to review complex cases and, when necessary perform procedures together This is similar to the “Heart Team” concept used in patients with complex coronary or structural heart disease that has become the widely accepted standard of care at tertiary care centers today The only drawback to the recent advances in endovascular treatments for PVD is the paucity of well-conducted controlled studies to investigate the effectiveness of new devices and techniques More clinical trials are needed to inform clinicians and patients on what

therapies provide the best short- and long-term outcomes

David R Holmes Jr This excellent manuscript offers an excellent synopsis of the actual as well

as the potential opportunities for treating a large number of patients with a variety of vascular diseases Training programs and Professional Societies continue to expand the role of

Cardiovascular physicians as part of the team based care of these patients

Acknowledgments

The authors gratefully acknowledge Katie Klein and Susan Nord of Aurora Cardiovascular Services for the editorial preparation of the manuscript, and Brian Miller and Brian Schurrer of Aurora Sinai Medical Center for their help in preparing figures

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