Medical Management and Revascularization In An Informative Case

1
Medical Management and Revascularization In An
Informative Case

• Ami A. Shah, MD
• Disclosures No Relevant Financial Relationships
  with Commercial Interests

2
Objectives

• Discuss current options for medical management
• Identify patients who could benefit from
  revascularization
• Evaluate merits and risks of surgical bypass
  versus angioplasty
• Recognize current limitations low sample sizes,
  lack of RCT, and few studies evaluating drug
  eluting stents

3
Presentation of Illness

• 29-year-old Caucasian female transferred to JHH
  for occasional amaurosis fugax without permanent
  visual loss and fatigue.
• PMH significant for HTN and biopsy proven
  membranous nephropathy postpartum with stable
  renal function
• 2 years ago during her C-section, BP could be
  measured only in her lower extremities.  
• Slow onset of fatigue
• Development of claudication in her upper
  extremities when she has to raise her arms above
  her head or comb her hair.
• Intermittent lightheadedness

4
Initial Evaluation

• Early 6/06, shortness of breath
• Labs hemoglobin 8 9, MCV 68, ESR of 111, and
  ferritin 75
•  
• Admitted to an outside hospital for CHF
• Echo EF 55, mild MR, grade I diastolic
  dysfunction and moderate aortic regurgitation
• Transferred to another institution
• Chest CT bilateral carotid artery stenosis and
  subclavian stenosis
• Angiogram extensive occlusions of main branch
  vessels off aortic arch

5
Initial Management and Transfer

• Started on prednisone 20 mg TID, a statin, and
  ASA for likely TA.
• Diuresed HTN managed with amlodipine,
  carvedilol, enalapril
• Transferred 6/14 to our institution due to unease
  taking care of a patient with Takayasus
• Felt a little bit better after starting
  prednisone but claudication symptoms persisted
• ANA negative, ANCA negative, creatinine 0.8
• Team agreed with the diagnosis of Takayasus
  arteritis

6
Additional History

• Social History  Works in a dentists office,
  lives in WV with 2 children and husband, no
  tobacco, alcohol, or illicits
• Family History  Hypertrophic cardiomyopathy,
  CAD, diabetes and hypothyroidism.  No autoimmune
  diseases.

7
Physical Examination

• Temperature 36.6 Celsius, pulse 74, BP 168/89
  measured in lower extremities, RR 18, O2 sat 98
  RA  
• Obese
• RRR, III/VI systolic ejection murmur at RUSB,
  I/IV diastolic murmur at RUSB, I/VI systolic
  murmur at the apex
• Carotid and subclavian bruits bilaterally
• Trace BLE edema
• No brachial or radial pulses bilaterally, 2 plus
  DP and PT pulses
• Normal CN and strength exam

8
Frequency of clinical features of Takayasu
arteritis at presentation and during the course
of disease
Kerr, G. S. et. al. Ann Intern Med
1994120919-929
9
Laboratory data

• K 5.6, BUN 51, creatinine 1.1 to 1.3
• WBC 14.7 with 89 neutrophils, hematocrit 36.5,
  MCV 74.8, RDW 21, platelets 414,000
• ESR 36, CRP lt 0.3
• pro-BNP 300
• Urinalysis no proteinuria and bland sediment
• Echocardiogram EF 65, trace MR and TR, moderate
  AR, and aortic root size upper limit of normal
• Chest x-ray obesity, normal cardiac silhouette.

10
JHH Admission 1 (6/14-17/06) Management

• Pulsed with 1 gram of methylprednisolone IV daily
  for 3 days
• Fatigability and claudication symptoms improved
• Cardiology recommended Q6 month echocardiograms
  to monitor aortic root size
• Discharged home on prednisone 60 mg daily,
  methotrexate at 0.6 mL subcutaneously weekly
  25mg/mL, folate, baby aspirin, her
  anti-hypertensive agents, a statin,
  levothyroxine, metformin, dapsone, Ca, and VitD
  with Vasculitis Center follow-up.

11
Readmission (7/15-22/06)

• At home several episodes of syncope after
  laughing and continued blurry vision.
• Readmitted to an outside institution and
  transferred to JHH
• Working hypothesis Likely sustained vessel
  damage from prior disease with extensive residual
  stenoses compromising cerebral perfusion pressure

12
MRI/MRA of chest and abdomen

• Ascending aorta at the pulmonary artery measured
  3.8 cm
• Markedly narrowed right and left common carotid
  arteries in the neck, right subclavian and
  axillary artery
• Left subclavian and axillary artery beyond the
  left vertebral markedly narrowed
• Right vertebral artery small but patent with
  surrounding increased T2 signal consistent with
  inflammation
• Mild narrowing of the celiac artery at its origin
  with mild post stenotic dilation.
• Patent SMA and no significant renal artery
  stenosis

13

• MRI demonstration of carotid wall thickening and
  lumen narrowing and beading, especially on the
  left.

14

• Mild narrowing of the celiac and SMA reported on
  MRI

15

• Mild dilatation of the aorta but no aortic wall
  thickening in this image.

16

• Right carotid artery thickening

17
Carotid duplex

• Left CCA occluded with no demonstrable flow.
• Left ICA and ECA not visible and presumably
  occluded. Small collateral vessels seen lateral
  to the expected location of the left CCA.
• Left subclavian and axillary arteries narrowed
  but not completely occluded.
• Right CCA markedly narrowed, gt70 stenosis. Wall
  of the right CCA markedly thickened
• Right vertebral artery exhibits retrograde flow,
  suggestive of a steal phenomenon.

18
Cardiac evaluation and management

• Leg SBP as high as 240
• Captopril and metoprolol doses titrated upward
  with a goal SBP of 160-180
• Repeat echo unchanged
• Tried to obtain angiography and cardiac
  catheterization records from VA to obtain
  pressures measured proximal and distal to her
  stenoses

19
Ophthalmic Evaluation

• Ophthalmodynamometry extremely poor retinal
  perfusion despite SBP 200s
• Fluoroscein angiography normal bilaterally

20
Vascular surgery

• Consulted given inactive disease detected on
  MRI/MRA.
• Good revascularization candidate but desired CTA
  of head, neck and chest which demonstrated
  similar findings to MRI/A.
• Left CCA displayed marked wall thickening and
  narrowing with the string sign which extends
  superiorly to approximately C3 level.
• Debated surgical bypass versus angioplasty /-
  stent

21
Medical Management
22
Corticosteroids

• 60 patients followed prospectively 1970-1990 at
  NIH
• 48 patients treated with GC alone or with a
  cytotoxic agent
• Remission achieved in 60 treated with prednisone
  alone at doses of 1mg/kg/day for 1-3 mos median
  time to remission 22 months
• gt50 relapse during taper
• Development of new lesions at previously
  unaffected sites is common
• 25 patients required addition of cytotoxic agents
• 23 of all treated patients never achieved
  remission

Kerr, G. S. et. al. Ann Intern Med
1994120919-929
23
Methotrexate

• Open-label pilot study of weekly low-dose MTXGC
• Outcomes Measured clinical characteristics,
  labs, angiographic findings, and ability to
  withdraw GC and MTX therapy
• Remission no clinical or new angiographic signs
  of active disease
• Subjects 18 patients entered 2 dropped out, 16
  followed for a mean period of 2.8 years (range
  1.3-4.8 years)
• Methods starting dose of methotrexate 15mg
  Qweek doses increased up to 25mg/week to achieve
  remission

Hoffman, G.S. et. al. Arthritis Rheum. 1994
Apr37(4)578-82
24
Methotrexate Results

• Weekly administration of MTX (mean stable dose of
  17.1 mg) and GC ? remissions in 81
• 7 patients (44) relapsed as GC tapered
• Retreatment led to remission. 3/7 successfully
  stopped GC
• Of those who achieved remission, 50 sustained
  remissions of 4-34 months (mean 18 months)
• 4 did not require GC or MTX for 7-18 months (mean
  11.3 months)
• 3 patients had disease progression in spite of
  treatment

Hoffman, G.S. et. al. Arthritis Rheum. 1994
Apr37(4)578-82
25
Azathioprine

• 1996-2001 15 of 65 consecutive newly diagnosed
  patients with TA not previously treated by any
  immunosuppressive therapy had active disease
• Active disease (2 or more) constitutional
  features, painful arteries, elevated ESR,
  elevated CRP
• Treatment Azathioprine 2mg/kg/day and
  prednisolone 1mg/kg/day for 6 weeks to be tapered
  to 5-10 mg/day by 12 weeks
• Angiograms before therapy and at one year
  follow-up

Valsakumar, A.K. et. al. J Rheumatol. 2003
Aug30(8)1793-8
26
Azathioprine Results

• All had complete resolution of systemic symptoms
• ESR and CRP decreased significantly at 3 months
• No change in peripheral pulses or limb BPs
• No progression or regression of lesions in any
  patient
• No new lesions identified

Valsakumar, A.K. et. al. J Rheumatol. 2003
Aug30(8)1793-8
27
Mycophenolate Case Reports

• Italian group with 3 patients with refractory TA
• Mycophenolate mofetil 1gm po BID.
• Clinical evaluation and WBC done weekly. Vascular
  lesions assessed by Doppler ultrasonography
• All 3 showed clinical benefit, and 2 resumed work
• Able to taper off steroid

Daina, E. et. al. Ann Intern Med. 1999 Mar
2130(5)422-6
28
Cyclophosphamide

• 20 TA patients prospectively followed for average
  4.6 yrs
• 16 with active TA treated with GC 8 responded
• 7 had poor response to prednisone (1mg/kg daily)
  after 3 mos
• 6/7 patients had clinical or angiographic
  progression on GC
• All 7 given cyclophosphamide 2mg/kg/day plus
  prednisone tapered to alternate day dosing
• 4/6 no progression of vascular lesions while on
  cyclophosphamide
• 2/6 progression of vascular lesions after 30 and
  48 mos of therapy

Shelhamer J.H. et. al. Ann Intern Med. 1985
Jul103(1)121-6
29
TNF Inhibitors

• Open-label trial of anti-TNF therapy at 3
  academic centers over 4.25 years
• 15 patients with active, relapsing TA (median 6
  yrs) on GC ( other immunosuppression in 13)
• Median prednisone dose required to maintain
  remission 20mg

• No other agents added to the treatment regimen
  concurrently
• If receiving cytotoxic agents, dosage not
  increased
• Clinical symptoms, physical exams, labs, and
  serial MRI

Hoffman, G.S. et. al. Arthritis Rheum. 2004
Jul50(7)2296-304
30
TNF Inhibitors

• 10 had complete remission for 1-3.3 yrs without
  GC.
• 4 had partial remission with gt50 reduction in GC
  dose.
• At 12 months followup, median dose of prednisone
  zero.
• Therapy failed in 1 patient.
• Repeated imaging revealed that 5 patients (2 CR,
  2 PR, and
• 1 treatment failure) had new lesions over 12
  month followup
• In 9/14 responders, increased anti-TNF dosage
  required to sustain remission.
• 2 relapses when etanercept interrupted. Remission
  reestablished upon restarting etanercept.

Hoffman, G.S. et. al. Arthritis Rheum. 2004
Jul50(7)2296-304
31
Revascularization Surgical Bypass Or
Percutaneous Intervention?
32
Revascularization

• Diagnosis occurs when stenotic and occlusive
  lesions already exist
• Such lesions are not reversible by medical
  management
• Often hemodynamically significant

Liang, P. et. al. Curr Opin Rheumatol. 2005
Jan17(1)16-24
33
Indications for revascularization

• Cerebrovascular disease due to cervicocranial
  vessel stenosis
• Coronary artery disease
• Moderate-severe aortic regurgitation
• Severe coarctation of the aorta
• Renovascular hypertension
• Limb claudication
• Progressive aneurysm enlargement with risk of
  rupture or dissection

Liang, P. et. al. Curr Opin Rheumatol. 2005
Jan17(1)16-24
34
Surgical Bypass
Liang, P. et. al. Curr Opin Rheumatol. 2005
Jan17(1)16-24
35
Percutaneous Revascularization
Liang, P. et. al. Curr Opin Rheumatol. 2005
Jan17(1)16-24
36
Surgical Bypass NIH Series 1970-1990

• 60 patients prospectively followed
• 68 had extensive vascular disease
• Stenotic lesions 3.6-fold more common than
  aneurysms (98 vs 27).
• ESR not a consistently reliable marker of disease
  activity.
• Bypass biopsy specimens from clinically inactive
  patients showed histologically active disease in
  44.
• Clinically significant palliation after bypass
• Medical therapy required for 80 20 had
  monophasic self-limiting disease.

Kerr, G. S. et. al. Ann Intern Med
1994120919-929
37
Vascular Procedures and Complications among 60
Patients with Takayasu Arteritis
Kerr, G. S. et. al. Ann Intern Med
1994120919-929
38
Surgical Bypass NIH Series 1970-1990

• 50 bypass procedures in 23 patients
• Median follow-up 5.3 yrs
• 24 restenosis rate, unclear how many
  hemodynamically significant
• 36 of 39 procedures using synthetic grafts
  complicated by restenosis
• 9 of 11 procedures using autologous vessels
  associated with restenosis

Kerr, G. S. et. al. Ann Intern Med
1994120919-929
39
Percutaneous Transluminal Angioplasty NIH Series
1970-1990

• 20 PTA procedures done in 11 patients
• PTA procedures most often done on subclavian and
  renal vessels
• Only 56 of angioplasties successful on the 1st
  attempt
• Only 33 succeeded on a 2nd attempt
• Restenosis occurred within 3.5 to 13.6 months.
• 3 patients eventually required bypass

Kerr, G. S. et. al. Ann Intern Med
1994120919-929
40
Cleveland Clinic 1979-2001

• Retrospective chart review of 20 TA patients
• Primary outcome measure patency of vessels by
  repeat invasive angiography or MRA
• Secondary outcome measures periprocedural
  complications, morbidity, and mortality
• Interventions bypass grafts, patch angioplasty,
  endarterectomy, percutaneous transluminal
  angioplasty (PTA), or stent placement.

Liang, P. et. al. J Rheumatol 200431102-106
41
Cleveland Clinic 1979-2001
Liang, P. et. al. J Rheumatol 200431102-106
42
Cleveland Clinic 1979-2001

• 62 revascularization procedures in 20 patients.
  Followup available for 52 procedures.
• 11/31 bypass grafts restenosed between 1 day to
  168 months after surgery
• 3/7 PTA restenosed after 1-72 mos
• 5/7 stents restenosed after 2-45 months
• No deaths
• CONCLUSION Despite providing short term benefit,
  endovascular revascularization procedures
  associated with a high failure rate in TA.

Liang, P. et. al. J Rheumatol 200431102-106
43
Renal Revascularization in TA-induced RAS

• 27 patients with TA-induced RAS underwent
  intervention
• Primary patency rates determined
• Late effects on BP, renal and cardiac function,
  survival analyzed
• All had HTN (mean BP, 167/99 mm Hg 2.5
  antihypertensive medications per patient).
• Mean estimated GFR in patients not receiving HD
  was 76 mL/min.
• 3 patients HD-dependent
• 2 had intractable congestive heart failure
• 40 interventions 32 aortorenal bypass, 2 repeat
  implantations, 4 nephrectomies, 2 transluminal
  angioplasties
• Autologous grafts in 20, prosthetic materials in
  12

Weaver, F.A. et. al. J Vasc Surg. 2004
Apr39(4)749-57
44
Renal Revascularization in TA-induced RAS

• Postoperative morbidity 19. No deaths.
• 3 graft stenoses, all due to intimal hyperplasia
  2 revised successfully
• 3 graft occlusions
• At 1, 3, and 5 years of follow-up, primary
  patency was 87, 79, and 79, respectively
• Decreased BP to a mean of 132/79 mm Hg (Plt.0001)
• Need for antihypertensive medications reduced to
  1/patient (Plt.01).
• Mean GFR increased to 88 mL/min (Plt.005)
• 2 patients no longer required HD.
• CHF resolved in both patients

Weaver, F.A. et. al. J Vasc Surg. 2004
Apr39(4)749-57
45
Surgical Outcomes 1955-1995

• Retrospective review of 106 consecutive patients
  with TA who underwent surgical treatment
• Ages 5 to 69 years (mean/-SEM, 31.7/-1.3 years)
• 12 early hospital deaths, all in patients
  operated before 1981
• Remaining 94 followed for a mean of 19.8 years
• 31/94 died CHF cause of death in 45
• Serious long-term complication anastomotic
  aneurysm, cumulative incidence at 20 years of
  13.8.
• Overall cumulative survival rate at 20 years was
  73.5.

Miyata, T. et. al. Circulation. 2003 Sep
23108(12)1474-80
46
Surgical Outcomes 1955-1995

• Patients classified according to Ishikawa
  prognostic criteria preop1, 15 year survival rate
  in Stage 3 patients was 82
• Complications retinopathy, severe HTN, grade 3
  or 4 AR, aneurysms2

1 Miyata, T. et. al. Circulation. 2003 Sep
23108(12)1474-80 2 Ishikawa, K. et. al.
Circulation. 1994 Oct90(4)1855-60
47
Surgical Outcomes 1955-1995

• Surgery seemed to increase the long-term survival
  of patients with stage 3 TA
• Conservative treatment recommended for stage 1 or
  2 disease
• Anastomotic aneurysms occur at any time after
  surgery ? need lifetime serial imaging to detect
  early aneurysms.

Miyata, T. et. al. Circulation. 2003 Sep
23108(12)1474-80
48
Coronary involvement

• 1972-2001 81/130 TA patients had selective
  coronary angiography 31 had abnormal coronary
  angiographic findings
• 24 coronary artery stenoses gt 75, 3 coronary
  artery-bronchial artery anastomoses, 3 aneurysmal
  coronary ectasias
• Among stenoses, ostium most frequently involved
  (87.5)
• 23/24 patients with stenoses treated surgically
• Mean follow-up 9.65 years, 100 follow-up rate
• 2 (8.7) in-hospital deaths and 3 (13) late
  deaths patency gt 85
• Actuarial survival rate 86.5 /- 7.3 at 5 years
  and 81.4 /- 8.4 at 10 years

Endo, M. et. al. J Thorac Cardiovasc Surg. 2003
Mar125(3)570-7
49
Subclavian artery angioplasty 1986-1995

• 61 SC artery angioplasties done in 55 consecutive
  patients with aortoarteritis (n 32) and
  atherosclerosis (n 23)
• PTA for 56 stenotic lesions and 5 total
  occlusions
• PTA successful in 52 (92.8) stenotic lesions and
  3 (60) total occlusions
• 3 patients (5.4) had complications, managed
  nonsurgically

Tyagi, S. et. al. Cardiovasc Intervent Radiol.
1998 May-Jun21(3)219-24
50
Subclavian artery angioplasty 1986-1995

• Patients with aortoarteritis
• younger
• female
• diffuse involvement
• Required higher balloon inflation pressures
• Had more residual stenosis
• Luminal diameter of stenoses were similar before
  PTA

51
Subclavian artery angioplasty 1986-1995

• Mean 43.3 mos follow-up of 40 patients
• Restenosis more often observed in aortoarteritis,
  particularly in those with diffuse arterial
  narrowing
• Lesions could be effectively redilated
• Clinical symptoms showed marked improvement after
  successful angioplasty.

Tyagi, S. et. al. Cardiovasc Intervent Radiol.
1998 May-Jun21(3)219-24
52
Balloon angioplasty for renovascular HTN

• PTA of renal arteries performed in 54 consecutive
  patients with hypertension and TA-induced RAS
• Angioplasty successful in 67 (89.3) of 75
  lesions attempted.
• Degree of stenosis decreased from 88.3 to 23.5
  (p lt 0.001)

Tyagi, S. et. al. Am Heart J. 1993 May125(5 Pt
1)1386-93
53
Balloon angioplasty for renovascular HTN

• Improvement in HTN (p lt 0.001) in 48 hrs
• After mean 26.4 mos follow-up, BP reduced to
  normal or improved in 93
• Angiographic restudy an average of 14 mos after
  restenosis at the same site in 7 of 52 (13.5)
  lesions

Tyagi, S. et. al. Am Heart J. 1993 May125(5 Pt
1)1386-93
54
Who benefits from revascularization?
1 Miyata, T. et. al. Circulation. 2003 Sep
23108(12)1474-80 2 Ishikawa, K. et. al.
Circulation. 1994 Oct90(4)1855-60
55
Summary of Bypass vs Angioplasty in TA

• Fibrotic, noncompliant vessels ? incomplete
  dilatation
• Need higher balloon inflation pressures and
  repeated inflation of the balloon
• Persistent inflammation at time of
  dilatation/stenting ? enhanced myointimal
  proliferation
• Stenotic lesions in TA long compared to the
  short, segmental lesions of atherosclerosis
• Bypass grafting has best long term patency rates
• Data with drug eluting stents needed

56
Back to our patient

• Decision made to taper glucocorticoids over 2
  months to 20mg daily and increase MTX to 17.5mg
  weekly
• Plan for surgical bypass to improve cerebral
  perfusion once at lower steroid dose
• Unable to taper beyond 30mg daily due to rising
  ESR

57
Operative Intervention

• 9/15/06 ascending aorta to left carotid
  bifurcation bypass with Dacron graft
• Left axillary artery explored for planned bypass
  to that vessel but thrombosed all the way out to
  the axilla
• Postoperative course unable to extend left wrist
  and fingers possibly due to brachial plexus
  injury during exposure of distal left axillary
  artery
• Visual symptoms resolved on POD 2