Phlebology Forum November - December 2012

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The Burden of Depression in Patients with Symptomatic Varicose Veins page 6

Paradoxical embolism, stroke and sclerotherapy page 9

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Dr. Nick Morrison

The Burden of Depression in Patients with Symptomatic Varicose Veins

Paradoxical Embolism, Stroke and Sclerotherapy

Contributing Editor/Reviewer: Felizitas Pannier

Contributing Editor/Reviewer: Eberhard Rabe, MD

Associate Editor: Diana Neuhardt, RVT, RPhS

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Associate Editor: Ted King, MD, FAAFP, FACPh

9

Contributing Editor/Reviewer: David J. Gillespie

Review of “Aspirin for Preventing the Recurrence of Venous Thromboembolism: The WARFASA STUDY”

Co-Contributing Editor/Reviewer: John Cullen, PhD

Contributing Editor/Reviewer: Thomas F. O’Donnell Jr. M.D.

Genetics of Venous Disease

Associate Editor: Jean-Jerome Guex, MD, FACPh

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Associate Editor: Lowell Kabnick, MD, FACS, FACPh

Outcomes of Venoplasty with Stent Placement for Chronic Thrombosis of the Iliac and Femoral Veins: A Single Center Experience

Incidence of and Risk Factors for Iliocaval Venous Obstruction in Patients with Active or Healed Venous Leg Ulcers

Contributing Editor/Reviewer: Steven M. Elias, MD, FACS, FACPh

Contributing Editor/Reviewer: Mark Meissner, MD

Associate Editor: Neil Khilnani, MD, FACPh

contents

From the Editor-in-Chief

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Associate Editor: Mark Meissner, MD

23

15

disclosure of interests

Name

ACP Role

Date Submitted

Disclosure

Stephanie Dentoni, MD

Recruitment & Retention (Chair)

6/25/12

Nothing to Disclose

Mark Forrestal, MD, FACPh

ACP

6/25/12

New Star Lasers Cooltouch: Speaker, Trainer

Jean-Jerome Guex, MD, FACPh

ACP BOD, Communications, Standing Committee, Leadership Development, UIP 2013 Task Force, AMA HOD Task Force, International Affairs (Chair),

6/14/12

Kreussler: Speaker; Sigvaris: Speaker, Investigator, Consultant; Innotech: Principal Investigator; Pierre Fabre: Consultant; Boerighr Ingelheim: Consultant, Medical Writer; Servier: Investigator, Consultant, Speaker

Lowell Kabnick, MD, FACS, FACPh

UIP 2013 Task Force

7/17/12

Angiodynamics: Consultant, Shareholder, Patent; Vascular Insights: Scientific Advisory Board

Neil Khilnani, MD, FACPh

ACP BOD, Member Services (Chair)

7/24/12

Sapheon: Data Safety Board Member

Ted King, MD, FAAFP, FACPh

ACP BOD, Leadership Development, PES-QM Task Force, Public Education

6/14/12

BTG: Investigator; Merz: Speaker

Mark Meissner, MD

ACP BOD, Education Standing Committee

7/13/12

Nothing to Disclose

Nick Morrison, MD, FACS, FACPh

UIP 2013 Task Force (Chair), Phlebology Forum Task Force (Chair), Annual Congress Planning Committee (Chair)

6/13/12

Medi: Speakers Bureau; Merz: Speakers Bureau; Sapheon: Principle Investigator; VeinX: Scientific Advisory Board

Eric Mowatt-Larssen, MD

ACP CME Committee

6/25/12

BTG International, Inc.: Consultant

Diana Neuhardt, RVT, RPhS

ACP BOD, Member Services, Audit, UIP 2013 Task Force, Phlebology Forum Task Force, Veinline, Recruitment & Tetention, CME, Distance Learning, Public Education (Chair)

6/15/12

Nothing to Disclose

Pauline RaymondMartimbeau, MD, FACPh

UIP 2013 Task Force

6/22/12

Nothing to Disclose

4

From the

Editor-in-Chief Dear Readers,

Following the very successful ACP Annual Congress, led by Diana Neuhardt and Julianne Stoughton, held in Florida November 15-18, we present the latest edition of Phlebology Forum with some interesting updates and new developments regarding aspirin therapy for VTE, the association of clinical depression with symptoms of varicose veins, neurosensory complications of foam sclerotherapy, treatment of chronic iliofemoral thrombosis, and the genetics of venous disease.

The reviews are written by recognized international experts with extensive experience with and insight into the subjects of each article.

Many of these reviewers and editors will be featured speakers at the International Union of Phlebology World Congress September 8-13, 2013 in Boston, USA. This meeting is expected to be the largest Phlebology meeting ever, with special programs such as simulation laboratories each day on models from sclerotherapy to IVC filters, and everything in between. Look for more updates in this publication throughout the year and plan on being a part of this important event next September.

Nick Morrison, MD Editor-in-Chief Phlebology Forum

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The Burden of Depression in Patients with Symptomatic Varicose Veins K. Sritharan, TRA Lane, AH Davies Eur J Vasc Endovasc Surg 2012-09-24 Contributing Editor/Reviewer: Felizitas Pannier, MD Associate Editor: Diana Neuhardt, RVT, RPhS

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SUMMARY In this well performed study the authors recruited 100 consecutive patients with a mean age of 52.7 years (63 women, 37 men) with symptomatic varicose veins who came to the vascular surgery outpatient clinic of Charing Cross Hospital in London. The patients were invited to complete validated questionnaires relating to quality of life and severity of the disease as well as a validated questionnaire concerning depression symptoms. Interestingly 29% of patients with symptomatic varicose veins had a depression score suggestive of depression. None of the patients were diagnosed or treated for depression before. The depression scores were not influenced by age or gender and there was no correlation with disease severity. The authors conclude that patients with symptomatic varicose veins are at increased risk of depression compared to the general population.

COMMENTARY The correlation of depression symptoms and symptomatic venous disease is not well investigated up to now. In an early study Blaettler reported a possible interrelation between venous symptoms and psychological findings (Blaettler 1991, Blaettler 1993). Blaettler and co-authors suggested the presence of a depressive-hypochondriac syndrome in some of the patients complaining about venous symptoms.

In the present study it is not clear if a higher prevalence of depression is linked to varicose veins or to venous symptoms. Several questions arise which should be investigated in further studies. In the general population depression is more prevalent in women compared to men. Why is this not the case in varicose patients? In principle the long-lasting presence of venous symptoms may cause a depressive syndrome itself. It could happen either on a psychological bases where the symptoms like heaviness and pain cause anxiousness and depression.

It is well known that venous ulcer patients have a higher incidence of depression. Alternatively microcirculatory changes and the chronic inflammatory process in the venous wall may also have an influence on

29% of patients with symptomatic varicose veins had a depression score suggestive of depression

neuro-physiologic mechanism.

On the other side venous symptoms like heaviness, feeling of swelling and pain which cause the patient to visit phlebologists are not very specific for venous disease. Patients with varicose veins may or may not have symptoms and patients with typical “venous symptoms� may or may not have varicose veins or other venous pathology. Patients with pre-existing depressive symptoms may more often link leg pain and heaviness to visible venous signs like varicose veins independently of their severity.

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Depressive circumstances could also be projected to the legs itself as the cosmetic appearance of the legs play an important role for well-being. By this other causes which lead to depression could be shifted to leg appearance and symptoms.

It would be very interesting to know if the successful treatment of varicose veins and venous symptoms would also lead to an improvement in the depression scores or if the depression score stays unchanged despite the improved venous situation.

Literature:

Blaettler W: Über einen eventuellen Zusammenhang zwischen Venenbeschwerden und psychischem Befinden. VASA (Suppl.) 1991; 32: 599 – 606

Blaettler W, Davatz U: Zur Psychogenese vermeintlich venös bedingter Beinbeschwerden. Phlebologie 1993; 22: 57 - 60

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Paradoxical Embolism, Stroke and Sclerotherapy Kurosh Parsi Phlebology 2012; 27: 147 - 167 Contributing Editor/Reviewer: Eberhard Rabe, MD Associate Editor: Ted King, MD, FAAFP, FACPh

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ABSTRACT In his paper Kurosh Parsi reviewed all published cases of stroke or pulmonary embolism associated with sclerotherapy. Since 1994 13 published cases of stroke and 5 cases of transitory ischemic attacks (TIA) after sclerotherapy have been reported. Four of the stroke events occurred after liquid and 9 after foam sclerotherapy. This very low incidence since 1994 indicates that stroke is a very rare event after sclerotherapy. In 10 of the reported 13 stroke cases patients recovered completely and with no long term defects. The most frequent risk factor was a right to left shunt and in particular a patent foramen ovale (PFO). In 5 patients paradoxical gas embolism with gas bubbles in the brain supplying arteries could be demonstrated. In these patients stroke symptoms occurred immediately after foam sclerotherapy. Paradoxical clot-embolism was suspected in 3 patients with a delayed onset of stroke symptoms.

COMMENT In the literature ischemic stroke is defined as an acute ischemic neurological deficit of presumed vascular origin associated with tissue infarction. A transient ischemic attack is a transient episode of neurological dysfunction caused by focal brain, spinal cord or retinal ischemia without acute infarction. The excellent review of the 13 published cases of stroke since 1994 in this review makes clear that we have to deal with two different entities which may have different consequences for the patients.

In the discussion of stroke reported after sclerotherapy we must distinguish strokes related to paradoxical clot embolism which has usually a delayed onset of symptoms and which has also been reported following various methods of treatment of varicose veins (Hartzheim 2000, Caggiati 2010) and strokes related to paradoxical airembolism with an early onset of symptoms as a more specific complication of foam sclerotherapy (Gillet 2011).

Late onset stroke associated with deep venous thrombosis may occur following liquid or foam sclerotherapy. In patients with a patent foramen ovale a paradoxical clot embolism and clot occlusion of cerebral arteries may occur.

Six such cases have been published since 1994.

A completely different pathology concerns stroke related to paradoxical air embolism with an early onset of symptoms within 20 minutes after injection. In these cases air bubbles may propagate through a PFO and then to cerebral arteries causing transient occlusion. In none of these early neurological complications reported as „stroke“ were intracerebral clots found. This entity does not correspond to thromboembolic pathology (Bush 2008). In contrary air bubbles could be demonstrated in cerebral arteries (Bush 2008). It is essential to note that all patients with stroke after sclerotherapy related to paradoxical air embolism have had complete or near complete recovery. To date no stroke with significant long term effects has been reported in these cases. (Gillet 2011).

However stroke and TIA must be differentiated from transient migraine-like visual events. Transient migraine-like symptoms may be observed after any kind of sclerotherapy, although they occur more frequently after foam than after liquid sclerotherapy (Guex 2005, Gillet 2009). Visual disturbances occurring after sclerotherapy may correspond to migraine with aura and not to transient ischaemic cerebro-vascular events. (Gillet 2010). They can be associated with paraesthesia and dysphasic speech disturbance depending on the extension of the cortical spreading depression, which is the pathological correlate of migraine with aura. Also in this entity it has been suggested that a right-to-left

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shunt (e.g. PFO), which is present in approximately 30 % of the general population, might be a factor, allowing air bubbles to pass into the arterial circulation (Morrison 2006) but here is no clear evidence of a relationship between bubbles and visual or neurological disturbances. Recent evidence has shown release of endothelin 1 from the vessel injected with liquid or foamed sclerosants. (Frullini 2011, Frullini 2012). Endothelin 1 is a vasoconstrictive substance released from the venous wall with a very short half life which is known to be associated to migraine.

In conclusion paradoxical clot embolism into cerebral arteries with stroke after sclerotherapy is an extremely rare event after liquid and foam sclerotherapy with six reported cases in literature since 1994. Paradoxical air embolism with a transient occlusion of cerebral arteries after foam sclerotherapy is also a very rare event with 7 published cases in literature. In most of the cases the neurological symptoms resolved within a few minutes or hours.

Sclerotherapy of varicose veins is a safe and efficient method in treatment of varicose veins. Taking the extremely high number of procedures worldwide into consideration stroke or TIA after sclerotherapy with liquid or foamed sclerosants is an extremely rare event.

Literature:

Harzheim M, Becher H, Klockgether: Brain infarct from a paradoxical embolism following a varices operation. Dtsch Med Wochenschr. 2000; 125: 794-796

Caggiati A, Franceschini M: Stroke following endovenous laser treatment of varicose veins. J Vasc Surg 2010; 51: 218-220

Gillet JL: Neurological complications of foam sclerotherapy: fears and reality. Phlebology 2011; 26: 277-279

Busch RG, Derrick M, Manjoney D. Major neurological events following foam sclerotherapy. Phlebology 2008; 23: 189 – 192

Guex JJ, Allaert F-A, Gillet J-L: Immediate and midterm complications of sclerotherapy: Report of a prospective multicenter registry of 12,173 sclerotherapy sessions. Dermatol Surg 2005; 31: 123-128

Gillet JL, Guedes JM, Guex JJ et al. Side effects and complications of foam sclerotherapy of the great and small saphenous veins: a controlled multicentre prospective study including 1025 patients. Phlebology 2009; 24; 131-138

Gillet JL, Donnet A, Lausecker M, Guedes JM, Guex JJ, Lehmann P: Pathophysiology of visual disturbances occurring after foam sclerotherapy.

Phlebology 2010; 25: 261-266

Morrison N, Cavezzi A, Bergan J, Partsch H. Regarding “stroke after varicose vein foam injection sclerotherapy”. J Vasc Surg 2006; 44: 224-225

Frullini A, Felice F, Burchielli S, Di Stefano R: High production of endothelin after foam sclerotherapy: a new pathogenetic hypothesis for neurological and visual disturbances after sclerotherapy. Phlebology 2011; 26: 203-208

Frullini A, Barsotti MC, Santoni T, Duranti E, Burchielli S, Di Stefano R: Significant endothelin release in patients treated with foam sclerotherapy.

Dermatol Surg. 2012; 38: 741-747

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Genetics of Venous Disease Author: Serra R Contributing Editor/Reviewer: David J. Gillespie Co-Contributing Editor/Reviewer: John Cullen, PhD Associate Editor: Jean-Jerome Guex, MD, FACPh

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Summary: In the current report Serra, et al extend their previous work by studying patients suffering from CVI in whom it was possible to construct a genealogical tree with at least three generations. They created a genealogical tree for each recruited family and obtained peripheral blood samples for DNA extraction from each member

CVI segregates in an autosomal dominant mode

of the recruited families. By the evaluation of genealogical trees they found that CVI segregates, in all families studied, in an autosomal dominant mode with incomplete penetrance. In nine of the families studied varicose veins were linked to the candidate marker

with incomplete penetrance.

D16S520 on chromosome 16q24 which they feel may account for the linkage to FOXC2.

Venous insufficiency and chronic venous ulceration cause a significant amount of suffering around the world and a notable economic impact on all societies. To date scientific investigation has not found any clear etiology for this disease. We know that patients have persistent ambulatory venous hypertension and chronic inflammation but don’t know how this develops over time and how to prevent it.

In this article by Serra, et al. we are one step closer to understanding and perhaps developing strategies to treat or prevent the disease formation. Over the past decade, mutations in the FOXC2 gene have been identified in patients with lymphoedema-distichiasis (LD) syndrome, an inherited primary lymphedema in which a significant number of patients have varicose veins123. In this group of patients, varicose veins were noted to have both early onset and increased prevalence compared with general population. Up to 49% of these patients had varicose veins with age of onset between 7 and 28 years2. This data suggested a possible developmental role for FOXC2 in both venous and lymphatic systems, although its exact role is unknown. Furthermore, patients with LD, and all their relatives who carry FOXC2 mutations but do not have clinical LD, have great saphenous vein reflux, supporting a role for FOXC2 in venous valve development1. This was the first gene to be implicated in the etiology of varicose veins.

Like most common diseases, it seems likely that CVI presents a multifactorial etio-pathogenetic mechanism and it is well established that approximately 80% of patients have a family history of the disease. A recent review by Anwar, et al, reveals that many gene variants have been identified that are thought to play a role

1 Mellor RH, Brice G, Stanton AW, French J, Smith A, Jeffery S, Levick JR, Burnand KG, Mortimer PS. Mutations in foxc2 are strongly associated with primary valve failure in veins of the lower limb. Circulation. 2007;115:1912-1920 2 Brice G, Mansour S, Bell R, Collin JR, Child AH, Brady AF, Sarfarazi M, Burnand KG, Jeffery S, Mortimer P, Murday VA. Analysis of the phenotypic abnormalities in lymphoedema-distichiasis syndrome in 74 patients with foxc2 mutations or linkage to 16q24. J Med Genet. 2002;39:478-483 3 Sholto-Douglas-Vernon C, Bell R, Brice G, Mansour S, Sarfarazi M, Child AH, Smith A, Mellor R, Burnand K, Mortimer P, Jeffery S. Lymphoedemadistichiasis and foxc2: Unreported mutations, de novo mutation estimate, families without coding mutations. Hum Genet. 2005;117:238-242

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in the development and progression of primary varicose vein disease4. These include varicose vein patients with mutations in the desmulin gene located at chromosome 15q26.3 which encodes for the desmulin protein that provides strength and integrity to the smooth muscle cell wall. Also, mutations of the hemochromatosis gene, including the common variants C282Y and H63D, cause deficiency of iron metabolism, which is known to exacerbate ulceration.

Although it has long been known that a family history can be used to identify a genetic predisposition to disease it is only recently that extraordinary technical advances in the field of human genetics have catalyzed an explosion of new information about the genetics of many diseases. The overall aim of human genetics research is the identification of mutations in the genome that will allow the prediction of the risk of diseases with the goal of preventing them from becoming symptomatic and allowing the patient to ultimately live a life free of disease. Genetic research in CVI has demonstrated the importance of many candidate genes in it’s development and highlights the need for a better understanding of the pathophysiological mechanisms that underlie disease development. The current study which provides further evidence for a role of FOXC2 also leads to many unanswered questions. Multiple lines of evidence have implicated FOXC1 and FOXC2 as central regulators of arterial cell specification during vascular development. Do their roles in CVI suggest that it may also be involved in venous cell specification during embryogenesis? If not during embryogenesis, is it possible that these mutations lead to abnormal signaling pathways in the venous system in adulthood? The identification of upstream and downstream regulators of FOXC2 may be a worthwhile avenue of investigation, inasmuch as the detection of the FOXC2 mutant in individuals with a family history of CVI may facilitate the decision to introduce either preventative or curative treatment by targeting FOXC2 or one or more of it’s regulators.

The work of the Serra group at the University Magna Graecia of Catanzaro, Italy is to be congratulated for its pioneering work. This line of investigation continues to suggest that there is a genetic component to venous disease. This new work indicates an autosomal dominant mode of inheritance with incomplete penetrance. As stated by the authors, further work is still necessary to identify other candidate genes and mechanisms. This will help us achieve a better understanding of the pathophysiology of varicose vein disease and to be able to conduct genotype phenotype analyses. This is an especially important step forward in our efforts to identify therapeutic targets and improve the treatment of patients with chronic venous disorders.

4 Anwar MA, Georgiadis KA, Shalhoub J, Lim CS, Gohel MS, Davies AH. A review of familial, genetic, and congenital aspects of primary varicose vein disease. Circ Cardiovasc Genet. 2012;5:460-466

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Review of “Aspirin for Preventing the Recurrence of Venous Thromboembolism:

The WARFASA STUDY” The New England Journal of Medicine, May 24, 2012 vol. 366 no. 21 Aspirin for Preventing the Recurrence of Venous Thromboembolism

Cecilia Becattini, M.D., Ph.D., Giancarlo Agnelli, M.D., Alessandro Schenone, M.D., Sabine Eichinger, M.D., Eugenio Bucherini, M.D., Mauro Silingardi, M.D., Marina Bianchi, M.D., Marco Moia, M.D., Walter Ageno, M.D., Maria Rita Vandelli, M.D., Elvira Grandone, M.D., and Paolo Prandoni, M.D., Ph.D., for the WARFASA Investigators* Contributing Editor/Reviewer: Thomas F. O’Donnell Jr. M.D. Associate Editor: Lowell Kabnick, MD, FACS, FACPh

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Traditionally venous disease has been divided into: 1) acute venous disease-deep venous thrombosis (DVT) and/or pulmonary embolus (PE) and 2) chronic venous disease-varicose veins, and venous ulcer. The concept around this classification has changed, so that idiopathic or unprovoked thromboembolic disease (not due to injury, surgery, immobilization, or oral contraceptives) now is approached as a chronic disease, which requires life-long prevention with medication1. Various drugs have been recommended as validated by randomized controlled trials, which balance the efficacy of DVT/PE prevention with the risk of major bleeding. One of the more recent trials, The WARFASA Trial, tested whether a daily low dose of aspirin (100 mg.) reduced the incidence of recurrent venous thromboembolic events in patients with a previous unprovoked and proximal (above the tibial veins) DVT or PE2.

The important consequence of this study is that an inexpensive well-studied drug like aspirin, which requires no monitoring, might have a superior safety profile and comparable efficacy to other drugs, such as Warfarin or newer drugs in the prevention of recurrent DVT and/or PE. This superiority study was conducted in a randomized double blinded manner, which compared aspirin to a placebo in an intention to treat protocol. Blinding is important in assessing the complications or safety of this medication, because blinding lowers the potential for bias from both the patient and the physician, who might ascribe adverse events (complications) to a medication with known side effects like aspirin.

Inclusion Criteria: Patients were eligible if this was their first episode of symptomatically and objectively confirmed idiopathic proximal deep vein thrombosis and/or pulmonary embolism. The trial included both patients treated initially with low molecular weight Heparin and a vitamin K antagonist as well as patients who underwent thrombolytic therapy.

Exclusion Criteria: The extensive exclusion criteria included: patients with demonstrated risk factors for venous thromboembolism; patients with active malignancy; recurrence of venous thromboembolism or bleeding episode during the six month treatment period with oral anticoagulants; patients with existing indications for treatment with aspirin or anti-platelet therapy; clear indication for long-term anti-coagulant therapy; treatment with nonselective nonsteroidal inflammatory drugs; active bleeding or high risk of bleeding as defined as gastrointestinal bleeding within the past 12 months or endoscopic diagnosis of peptic ulcer disease or ulcerative esophagitis within the last six months; and finally, intracranial bleeding within the past year. These exclusion criteria were similar to trials using oral anti-Xa factor treatment – the Einstein Extension Study and the Re-Sonate Study.

Safety-Adverse Events: As shown below in Table I, the WARFASA study reported a low complication rate in the aspirin arm, which was no different than the placebo arm [five major bleeding or clinically relevant non-major bleeding episodes in each group]. This particular adverse event rate is lower than trials where aspirin has been compared to placebo in other cardiovascular studies, as best demonstrated in a systematic analysis by Rodrigues and associates of aspirin use in cardiovascular studies. In that review severe gastrointestinal events increased twofold over control and a dose relationship was suggested.

1 Goldhaber SZ. Prevention of Recurrent Idiopathic Venous Thromboembolism Circulation. 2004; 110: IV-20-IV-24 2 Becattini C, Agnelli G, Schenone A, Eichinger S, et al. Aspirin for Preventing the Recurrence of Venous thromboembolism. N Engl J Med 2012; 366:1959-67

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TABLE I ADVERSE EVENTS IN THE CURRENT STUDY TYPE

CONTROL

ASPIRIN

P VALUE

Non-fatal major bleeding

1 (gastric ulcer)

1 (angiodysplasia)

-----

Non-major bleeding

3 (gastritis; trauma)

3 (gingival; skin)

-------

“Drug-Related” gastric pain

2

1 1 Renal Failure 1 cutaneous reaction

Death

5 (1.3%/yr.)

6 (1.4%/yr)

Sudden– adjudicated to PE

1

1

Efficacy: This study used a combined endpoint of symptomatic DVT and PE. Combined endpoints are frequently used in contemporary trials, when each of the individual end points has a low event rate, particularly in the placebo arm. The combined end point may permit lower study enrollment numbers, as dictated by the power calculation and also a greater probability of achieving statistical significance. Each of the individual endpoints differed as to statistical significance on their own. Overall 71 (8.6%) patients in the trial had either a DVT (44 patients) or PE (27 patients) of which two were fatal (one in each arm). Moreover, the type of unprovoked initial venous thromboembolic event influenced the nature of the subsequent recurrence. An initial PE carried with it a greater treatment effect of aspirin on recurrent PE than those with an initial DVT on a recurrent DVT. Hazard ratios (HR) were the efficacy measure employed to show the statistical superiority of aspirin over placebo in this trial.

HR is used when a time to event or survival data is employed and this metric differs from relative risk ratios (RR).

The hazard ratio is an expression of the hazard or chance of events occurring in the treatment (aspirin) arm as a ratio to the hazard of the events occurring in the placebo arm. By contrast, the RR is an index of how many events occurred in a trial expressed as the ratio of the proportion of events occurring in the treatment (aspirin) group compared with that in the control (placebo) group. This ratio should only be calculated at the end of the clinical trial and the cessation of the trial should be pre-specified as it was in this trial. RR differs from absolute risk, which is the actual risk of developing DVT over a specific time.

The hazard ratio for efficacy-prevention of recurrent venous thromboembolism is shown in the following table.

It is interesting to note that the HR was not significant for prevention of recurrent DVT in patients with an initial episode of DVT.

TABLE II ADVERSE EVENTS IN THE CURRENT STUDY OUTCOME MEASURE

HAZARD RATIO (95% CI)

P VALUE.

Recurrent VT (overall)

0.58 (0.36 to 0.93)

0.02

Recurrent PE ,initial PE

0.38 (0.17 to 0.88)

0.02

Recurrent DVT, initial DVT

0.65 ( 0.65 to 1,20)

0.17

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Comments on study design This RCT undertook a mid trial change in its endpoint. While highly unusual, this was rationalized on the basis of being consistent with other contemporary studies on the prevention of recurrent thromboembolism, as shown in the table below. Recruitment was slow in the trial, so that over six years was required to conduct the trial, where subtle changes in the management of these patients not controlled by the trial design may have occurred. This phenomenon has been well recognized in cardiovascular trials. Although the criteria for establishing recurrent DVT was by well recognized duplex criteria, the diagnosis of PE was by both diagnostic studies and adjudication by a panel. Not all patients underwent spiral CT as far as the diagnostic evaluation for PE and some received ventilation perfusion scans which may lead to an overestimation of the incidence of PE.

TABLE III COMPARISON TO OTHER STUDIES STUDY

Recurrent VTE

Major Bleeding

Aspirin (100 mg)

13.6

2.4

Placebo

21.8*

2.5

(DRUG/NAME)

WARFASA2

ELATE

NUMBER

LENGTH

403

24

(PATIENTS)

738

3

(MONTHS)

(%)

(%)

28

Warfarin (INR 2.0-3.0)

1.6

2.1

Warfarin (INR 1.5-1.9)

4.3*

2.4

5.4

1.9

14.6*

.079

Rivaroxaban 20 mg

1.3

0.7

Placebo

7.1*

0

Dabigatran 150 mg (BID)

0.4

0.3

Placebo

5.6*

0*

Dabigatran 150 mg (BID)

1.8

0.9

Warfarin > INR 2-3

1.3*

1.8

PREVENT4

525

25

Warfarin (INR 1.5-2.0) Placebo Einstein extension5

Re-Sonate

Remedy

6

7

1196

1343

2856

6-12

6

UP TO 36

* = statistically significant

COMMENT Treatment with an anticoagulant medication balances the risk of bleeding versus the preventative effects against venous thromboembolism in patients with idiopathic or unprovoked DVT/PE. The results with other drugs in comparison to aspirin are shown above in Table III. Initial trials compared Warfarin at standard INR goals to lower INR ranges. The incidence of major bleeding complications varied little in the ELATE Trial with warfarin at standard

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and low intensity doses3 and the low intensity Warfarin arm of the PREVENT Trial4. The later trial was stopped after two years as a result of the major benefit enjoyed by the Warfarin arm (VTEďƒ Control = 7.2 /100 patient years vs. 2.6/100 patient years Warfarin arm). Despite an approximately 60% reduction in the relative risk of VTE, Warfarin requires close monitoring and careful dose adjustments. As demonstrated in Table III, trials with the oral factor Xa inhibitor, rivaroxaban5 and the oral thrombin inhibitor, dabigitran67 have been shown to be effective in reducing the risk of VTE by nearly 80%. While requiring no monitoring, these oral agents are expensive and await more extended post- market evaluation of bleeding risks in a real world setting. It is difficult to directly compare these agents in these RCTs to aspirin in the WARFASA trial, because the trial length in the Re-Sonate and the Einstein Extension studies was much shorter (6 months) than the WARFASA trial (24 months) and the Re-Sonate study was a non-inferiority trial. Such a difference in the longer follow-up period of the WARFASA trial can lead to higher cumulative VTE and major bleeding event rates in that trial. The WARFASA trial suggests that an antiplatelet drug, aspirin, is effective in lowering the risk of recurrent DVT/PE with a well defined safety profile.

3 Kearon C, Ginsberg JS, Kovacs MJ, Anderson DR, Wells P, et al. Comparison of low-intensity warfarin therapy with conventional-intensity warfarin therapy for long-term prevention of recurrent venous thromboembolism.N Engl J Med. 2003 14;349(7):631-9.

4 Ridker PM, Goldhaber SZ, Danielson E, et al. For the PREVENT Investigators. Long term, low intensity warfarin therapy for the prevention of recurrent thromboembolism. N Engl J Med 2003;348:1425-434 5 EINSTEIN Investigators: Bauersachs, Berkowitz R, Brenner B, Buller HR, et al. Oral rivoroxaban for symptomatic venous thromboembolism. N Engl J Med 2010; 363:2499-510.

6 Shulman S, Baanstra D, Eriksson H, et al. Dabigatran versus placebo for extended maintenance therapy of venous thromboembolism. J Thromb Haemost 2011;9(s2):037.

7 Shulman S, Eriksson H, Goldhaber SZ et al. Dabigatran or warfarin for extended maintenance therapy of venous thromboembolism. J Thromb Haemost 2011;9 (s2):731.

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Outcomes of Venoplasty with Stent Placement for Chronic Thrombosis of the iliac and Femoral Veins:

A Single Center Experience Kurklinsky AK, Bjarnason H, Friese JL, Wysokinski WE, McBane RD, Misselt A, Moller SM, Gloviczki P. J Vasc Interv Radiol. 2012 Aug;23(8):1009-15. Epub 2012 Jun 13.

Contributing Editor/Reviewer: Steven M. Elias, MD, FACS, FACPh Associate Editor: Neil Khilnani, MD, FACPh

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ABSTRACT This report analyzes the outcomes of stent placement in a very narrow and specific set of patients. The only patients included were those with iliac and /or common femoral vein disease. Any patients with IVC involvement or acute on chronic disease were excluded. 89 out of a potential 189 met the above criteria.

The purpose of the study was focused in that it was done to assess 30-day, 1-year and 3-year patency rates.

Median follow up was 11.3 months. Primary patency at 1 and 3 years was 81% and 71%. Primary assisted patency was 94% and 90% at 1 and 3 years. Secondary patency was 95%. While there is no data regarding VCSS or other QoL measures, the authors felt that pain and ulcers improved more than edema did post procedure. There were no bleeding complications. Their conclusion was that in this select group of patients angioplasty/stenting is safe with acceptable patency rates.

CoMMENTARY This paper essentially echoes what previous studies have shown including the largest series by Neglen and Raju (1).

Only successful procedures are reported. The authors make the point that they are a “quaternary” referral center.

It would have been interesting to know what their success rate was when treating cases that others either elected not to or had failed. There is no mention of IVUS within the article which can be interpreted in two ways: IVUS is not needed for those procedures or IVUS is needed for these procedures to be more successful. (I.e. increased primary patency rate) This reviewer has a bias towards the use of IVUS which can be helpful in: defining extent of disease, adequate stent placement, adequate stent deployment and dilation etc. Others report acceptable outcomes without IVUS. Selected use of IVUS is probably the best compromise.

Various types of stents were utilized, all with decent success. While a lot of recent discussion within the venous community has been about a “venous specific stent”, the Mayo group had good results with: Wallstents, Protégé, SMART and Luminexx. Stent sizes tended to be a little smaller than other series, for instance, only 4 limbs received 16mm stents. Yet, one cannot dismiss the relatively good reported results.

When discussing stent placement at various meetings the status of inflow (femoral vein, profunda vein) and outflow (IVC) is routinely highlighted. In this series we can assume outflow (IVC) was adequate at least by venography otherwise these patients would have been excluded. The only mention of inflow in this study is that patients with prior inflow were kept anticoagulated longer.

Aside from procedural success, pain and ulceration appeared to improve more than edema. This is important in setting patients expectations for those procedures. Stent placement is not a panacea for these relatively young patients whose average age in this series was in the mid 40’s. As in all venous interventions the improvement in quality of life is most important.

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In summary this series teaches us that:

1. End stage chronically occluded disease can be treated.

2. A “bare bones� approach can be successful and perhaps more economical.

3. IVUS may not be needed as often as some think.

4. Various stent types can be used with success.

5. Pain and ulceration improve more than edema.

6. Patients rarely have complications and are rarely made worse by intervention.

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Incidence of and Risk Factors for Iliocaval Venous Obstruction in Patients with Active or Healed Venous Leg Ulcers Marston W, Fish D, Unger J, and Keagy B J Vasc Surg 2011; 53: 1303-8 Contributing Editor/Reviewer: Mark Meissner, MD Associate Editor: Mark Meissner, MD

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Venous ulceration is the most severe manifestation of chronic venous disease and will recur in 100% of noncompliant patients within 3 years. Interventions proven to be effective in reducing the incidence of recurrence include the use of compression stockings and removal of an incompetent superficial venous system. However, despite these interventions, ulcers may recur in as many of 12% of patients within 12 months. Efforts to prevent recurrent ulceration in these patients have led to a proliferation of interventions of unproven value such as ablation of incompetent perforators. The authors of this manuscript sought to identify the incidence of occult iliocaval venous obstruction as a cause of venous ulceration and its recurrence.

The authors used CT or MR venography to evaluate for the presence of occult iliocaval venous obstruction in 64 patients (78 limbs) with C5-6 disease. Using standard ultrasound criteria, reflux was present in the deep, superficial, or both systems in 13%, 38%, and 49% of limbs respectively. However, occult iliocaval venous obstruction of > 50% diameter reduction was identified in 37% of patients, including complete occlusion in 9% of patients and > 80% stenosis in another 14% of patients. Notably, abnormal ultrasound findings in the common femoral veins (diminished respiratory variation and flow augmentation with compression) had a sensitivity and specificity of 77% and 100% for identification of a > 80% stenosis by cross sectional imaging. Women were more likely to have iliocaval venous obstruction, as were those with a history of DVT (12.3 X increased risk) or deep venous reflux (17.7 X increased risk). Based upon their findings, the authors suggest that patients with abnormal common femoral waveforms on duplex ultrasound go directly to percutaneous venography and intervention, while those with a history of DVT or deep venous reflux should go further evaluation with CTV or MRV. Limbs with isolated superficial reflux likely require no further evaluation.

Although previous studies have documented a significant incidence of iliac vein compression in normal populations undergoing CT of the abdomen, this is the first study to evaluate the incidence of potentially clinically important

...those with a history of DVT or deep venous reflux should go further evaluation with CTV or MRV

iliac vein obstruction in patients with active or healed venous ulceration, all of whom are at high risk of recurrence. More than one-third of such patients will have > 50% obstruction and almost one-quarter > 80% obstruction of the iliocaval venous outflow. This study further demonstrates that although the specificity of ultrasound for the identification of iliocaval venous obstruction is high, its sensitivity is inadequate to exclude proximal venous obstruction in these patients. Finally, the study also identifies patients in whom further evaluation for iliocaval venous obstruction should be especially considered – women, patients with a history of DVT, and those with axial deep venous reflux.

Unfortunately, as the authors acknowledge, despite identifying iliocaval venous obstruction as a potentially important problem in this patient population, the study does leave several questions unanswered. Important

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among these are the optimal patient population to be considered and the best modality to evaluate them. CT and MR venography are useful in identifying iliac vein obstruction in some patients, although both are static imaging modalities that are unable to account for possible influence of activity in the upright position and cardiac and respiratory variability. The sensitivity of cross sectional imaging in relation to more invasive studies such as venography and intravascular ultrasound is unknown. Finally, the utility of correcting iliocaval venous obstruction in patients with recurrent ulcers or ulcers recalcitrant to optimal treatment is not addressed in this study.

The optimal management of patients with C5-6 disease continues to evolve, with strong evidence supporting the utility of compression and superficial venous surgery in preventing recurrence. However, the importance of underlying iliocaval venous obstruction is only beginning to be appreciated, as are the appropriate diagnostic modalities for its diagnosis. This study is important in bringing attention to the potential importance of proximal venous obstruction in managing these patients. Future work should be directed towards identifying those patients most likely to benefit from identification of these occult abnormalities (recalcitrant and recurrent ulcers) and the optimal modalities for doing so.

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intellectual capital

/// UIP 2013 Call for Abstracts

World Meeting of the International Union of Phlebology /// September 8–13, 2013

Call For Abstracts The Scientific Committee of the International Union of Phlebology invites you to submit an abstract for consideration at the 2013 World Congress of the International Union of Phlebology, September 8–13, 2013 in Boston, MA. Please submit an abstract on any of the following topics:

+ BASIC SCIENCE + CCSVI + CHRONIC VENOUS INSUFFICIENCY AND VENOUS ULCERATION + COMPRESSION THERAPY + DEEP VENOUS THROMBOSIS + EPIDEMIOLOGY + LYMPHADEMA + MISCELLANEOUS

+ PELVIC VENOUS DISEASE - REFLUX & OBSTRUCTION + PHLEBOLOGIC NURSING + SUPERFICIAL VENOUS DISEASE » Venous Ablation » Sclerotherapy » Miscellaneous + VENOTONIC DRUGS + VENOUS DIAGNOSTICS + VENOUS MALFORMATIONS

Deadline for Submission is April 15, 2013 Abstracts must be submitted online and are limited to 250 words.

For additional details and to submit an oral or poster abstract for presentation at UIP 2013, please visit http://ww4.aievolution.com/acp1301/

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