Transcript The Changing Paradigm of Renal Artery Stenosis

Renal Artery Stenosis – The Good,
The Bad and The Different
Rick Stouffer MD
University of North Carolina
Disclosure
I will discuss off-label uses
 No financial conflicts of interest

The ‘classic’ patient for renal artery
revascularization
55 year old male
 HTN, known CAD (prior PCI)
 Admitted with CP/SOB, BP 194/124 mm Hg
 BP Rx: ACEI, beta blocker, nitrate
 Creatinine 1.6 mg/dl, HCT 41.8%
 Referred for cardiac catheterization
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Renal angiography +
hemodynamic assessment
Aorta
Right renal artery
Renal artery revascularization
• Accelerated HTN
• Mild elevation in
creatinine
• Symptoms
Did We Benefit This Patient?
Outline
Types of RAS
 Atherosclerotic RAS
 Natural history of the patient with RAS
 Treatment of RAS
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Renal Artery Stenosis
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Atherosclerotic (90%)
Fibromuscular dysplasia (10%)
– Medial fibroplasia (90%)
» classic "string of beads" appearance
» middle-to-distal portion of the artery
– Perimedial fibroplasia
» focal stenoses
– Intimal/Medial fibroplasia
» a focal, concentric stenosis
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Aortorenal dissection
Vasculitis involving the renal artery (i.e. PAN)
AVMs involving the renal artery
Irradiation of the renal artery
Scleroderma
FMD – Anatomy and Pathophysiology
70 year old female with chest pain
and 4-drug hypertension.
Circulation. 2005;112:e278-9.
Before balloon angioplasty
After balloon angioplasty
A Cautionary Tale
37-year-old male admitted with headache of six
months duration that had worsened in the last week
and was accompanied by blurry vision, dyspnea on
exertion and weakness in his legs.
 No significant PMH, was not taking any
medications and had never been diagnosed with
hypertension. No history of alcohol or drug use.
 FH - mother with hypertension and a sister with
migraine headaches.
 Brachial BP was 252/160 mm Hg with no significant
difference between arms.

A Cautionary Tale
BP = 252/160 mm Hg
 Ophthamology consultant - Grade IV retinopathy
including marked AV nicking and venous dilatation,
cotton wool spots, large areas of choroidal
ischemia, delayed vascular filling, blind spots and
papilledema in both eyes.
 MRI of the brain - No evidence of intracerebral
mass but increased signal abnormality within the
pons, consistent with hypertensive encephalopathy.
 MRI/MRA of the abdomen showed normal kidney
size, no renal or adrenal masses and ‘No evidence
of renal artery stenosis.’
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FMD not visualized on MRI/MRA
Balloon angioplasty with resolution of pressure gradient
J Invasive Cardiol. 2007;19:E31-3.
5 years later - He has run marathons and climbed Mount
Kilimanjaro. Home systolic BPs of 130 mm Hg on HCTZ 20 mg
daily, enalapril 10 mg daily and Norvasc 10 mg twice daily.
Outline
Types of RAS
 Atherosclerotic RAS
 Natural history of the patient with RAS
 Treatment of RAS
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Atherosclerotic RAS
• Usually ostial
• Associated with diseased
aorta
• Can be unilateral or
bilateral
Prevalence of Atherosclerotic RAS
– 6.8% in healthy adults > 65 years old
– Evaluation with renal artery duplex of 834 patients consecutive patients
who were participants in the Forsyth county cohort of the Cardiovascular
Health Study (J Vasc Surg. 2002;36:443–51).
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Unselected autopsies
Hypertensives
Aged 65 years and older
Diabetics
4-27%
1-4%
6.8%
8%
RAS is common in patients
with vascular disease

Prevalence of RAS
– Proven MI
12%
– Undergoing cardiac catheterization 6-19%
– Lower extremity PVD
22-59%
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Predictors of RAS in patients undergoing cardiac
catheterization
– CAD; Age; PVD; serum creatinine; hypertension
Traditional Paradigm of
Renal Artery Stenosis
Severe HTN
Physiologic
testing for RAS
Renal Angio
(anatomic)
Revascularization
The Changing Paradigm of
Renal Artery Stenosis
Chest pain,
dyspnea, etc
Severe HTN
Evaluation for
Vascular Disease
(usually CAD)
Physiologic
testing for RAS
Renal Angio
(anatomic)
Revascularization
Outline
Types of RAS
 Atherosclerotic RAS - Prevalence and 'Risk factors'
 Natural history of the patient with RAS
 Treatment of RAS
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A tale of two patients
RAS is a marker of a poor prognosis
Dismal Prognosis Associated with RAS
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3 year mortality
– 26% in patients treated with stents (Circulation 1998;98:642-647)
– 28% in patients managed medically (Mayo Clin Proc 2000;75:437)
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4 year mortality
– 43% in patients with RAS discovered incidentally at cardiac
catheterization (Kidney International 2001;60:1490-1497)
– 35% in patients with RAS discovered incidentally at cardiac
catheterization (JASN 1998;9:252-256)
– 26% in a multi-center study of patients undergoing percutaneous
renal revascularization (Circulation 1998;98:642-647)
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5 year mortality
– 33% in a single-center study of patients undergoing percutaneous
renal artery revascularization (Catheter Cardiovasc Interv. 2007;69:1037)
Effect of RAS on Prognosis –
Relative Five year Survival
100
Survival
80
60
40
20
0
Breast
Cancer
RAS
Colorectal
Cancer
Non-Hodgkins
Lymphoma
Ries LAG et al. SEER Cancer Statistics Review, 1973-1998.
National Cancer Institute. September 2000.
Clinical Events in Patients With RAS
Claims data from a 5% random sample of the United States Medicare population were used
to select patients without atherosclerotic renovascular disease in the 2 years preceding
December 31, 1999 (N= 1,085,250), followed until December 31, 2001.
J Am Coll Cardiol Intv 2009;2:175-182
The $64000 Question
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Is RAS a marker of severe atherosclerosis and thus
portends a poor prognosis?
or
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Does RAS contribute to progression of vascular
disease - thus implying that effective treatment may
improve clinical outcomes?
Outline
Types of RAS
 Atherosclerotic RAS
 Natural history of the patient with RAS
 Treatment of RAS
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Optimal Medical Treatment
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ARB + diuretic to get BP to
target
– <140/90 mm Hg
– <130/80 mm Hg with DM
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LDL to goal
– Currently <100 (or 70) mg/dl
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Diabetes Management
– HbA1c to target (<7%)
Smoking Cessation
 Anti-platelet therapy (aspirin
+/- clopidogrel/prasugrel)
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What role does revascularization play?
Percutaneous Treatment of RAS
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1978 - Gruentzig and colleagues report first balloon
angioplasty of renal artery stenosis
– Gruentzig A, Kuhlmann U, Vetter W. Treatment of renovascular
hypertension with percutaneous transluminal dilatation of a renal
artery stenosis. Lancet 1978; 1:801-802.
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Fall 1978 - first renal artery angioplasty in US at UVa. Patient referred by Carlos Ayers to Charles Tegtmeyer who
obtained angioplasty balloon from Gruentzig in exchange
for fishing equipment.
– Tegtmeyer CJ, Dyer R, Teates CD, Ayers CR, Carey RM, Wellons
HA Jr, Stanton LW. Percutaneous transluminal dilatation of the
renal arteries: techniques and results. Radiology 1980;
135(3);589-599
Treatment of RAS
EP
EP
Stents
Stents
PTRA
PTRA
Surgery
Surgery
1950
1960
1970
1980
1990
2000
2010
Evidence-based Medicine
Evidence-based Medicine
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Reviewed 55 studies
“Almost two thirds of the studies that we reviewed were of
poor methodologic quality; none was deemed to be of
good quality.”
“More than half of the studies had limited applicability to
patients commonly seen in practice or to modern
management strategies.”
“No study directly compared angioplasty with stent
placement and "aggressive" medical treatment with
currently available antihypertensive, antiplatelet, and lipidlowering agents.”
Effect of RA Revascularization on HTN
Study
Device
 Klinge
stent
 Lossino stent
 DRASTIC balloon
 Rocha
stent
 Dorros
stent
N
134
153
106
150
145
Cure Improved
10%
68%
12%
51%
7%
68%
6%
50%
1%
52%
Effects of RA Revascularization on Ischemic
Nephropathy
Prog Cardiovasc Dis 2007;50:136
Angioplasty and STent for
Renal Artery Lesions
NEJM 2009;361:1953-1962
ASTRAL Trial
Substantial atherosclerotic RAS
Suitable for endovascular revascularization
Patient's doctor was uncertain that the patient would
benefit from revascularization
Revascularisation
(n = 403)
with angioplasty and/or stent
(and medical treatment)
No revascularisation
(n = 403)
Medical treatment according to
local protocol
PATIENT CHARACTERISTICS
Revasc.
Medical
P-value
70 (42 – 86)
71 (43 – 88)
0.7
Male
63%
63%
0.9
Current smoker
20%
22%
0.5
Diabetes
31%
29%
0.5
CHD
49%
48%
0.2
PVD
41%
40%
0.7
GFR (ml/min)
40.3
39.8
0.7
(5.4 – 124.5)
(7.1 – 121.7)
Mean age (range)
Blood Pressure, Cholesterol, Stenosis
Procedural Complications
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38 periprocedural complications in 31 of the 359 patients
(9%) who underwent revascularization (including 1 of the
24 patients in the medical-therapy group who crossed over
to revascularization)
Nineteen of these events (in 17 patients) were considered
to be serious complications
– Pulmonary edema (1) and Myocardial infarction (1)
– Renal embolizations (5), Renal arterial occlusions (4) and Renalartery perforations (4)
– Femoral-artery aneurysm (1)
– Cholesterol embolism leading to peripheral gangrene and
amputation of toes or limbs (3)
Medications at One Year
Revasc.
Medical
P-value
Any Anti-hypertensives
97%
99%
0.03
Diuretic
64%
69%
Ca2 antagonist
63%
71%
Beta-blocker
46%
55%
0.02
ACE-I, A-II antagonist
50%
43%
0.05
Alpha-blocker
39%
38%
Mean no. anti-hypertensives
2.77 (1 - 6) 2.99 (1 - 6)
0.03
Blood Pressure
Serum Creatinine
Clinical Events
Survival
• “An important limitation of our trial concerns the population that we
studied. As noted, patients were enrolled in the trial only if their own
physician was uncertain as to whether revascularization would
provide a worthwhile clinical benefit.”
• Patient selection (single center)
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–
–
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508 patients with atherosclerotic renovascular disease
Of these, 283 patients had renal-artery stenosis of more than 60%
71 underwent randomization
24 underwent revascularization outside the trial
• poorly controlled hypertension
• rapidly declining renal function,
– 188 received medical treatment only.
RAS and stenting – has the question been
answered?
Criticisms of ASTRAL
1. Selection bias and inexperienced operators
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‘On average, 2 patients per center per year underwent
randomization, which indicates serious selection bias or
inexperienced staff at centers with very low intervention
rates. This concern is supported by a low rate of technical
success (317 of 403 patients [79%] in the revascularization
group) and a high rate of serious complication in 23 of 280
patients (8%) as compared with reports in the literature of
98% and 2%, respectively.’
NEJM 2010;362:762
Criticisms of ASTRAL
2. There was a reduction in the number of
antihypertensive drugs in stent treated patients
 ‘The study design implies that optimal medical therapy was
used to achieve normalized blood pressure in both groups.
Thus, not only the blood pressure values but also the
number of antihypertensive drugs used to achieve this
goal should be taken into account. The … significantly
lower number of antihypertensive drugs administered in
the revascularization group (P=0.03) preclude the
definitive conclusion that renal-artery revascularization
provides no clinical benefit.’
NEJM 2010;362:762
Criticisms of ASTRAL
3. Patients with severe RAS were not enrolled
 ‘The results of the ASTRAL investigation should be read
and interpreted critically. As with the COURAGE (Clinical
Outcomes Utilizing Revascularization and Aggressive Drug
Evaluation) trial, the take-home message should be that
for patients with a moderate degree of renal-artery
stenosis, medical management is as effective as
revascularization over a 5-year follow-up period. Patients
seen as requiring anatomical correction were not enrolled;
only those deemed suitable for randomization to stenting
or medical therapy were included. Thus, the patients most
likely to benefit from stenting (those with subocclusive
lesions or with very severe disease in one or both kidneys)
were not part of this study.’
NEJM 2010;362:762
Criticisms of ASTRAL
4. More concern about high complication rate
‘Another concern is the prohibitively high rate of
amputation and embolization in this study. This
calls into question the appropriateness and safety
of the techniques currently used to perform the
procedure. In more than 200 consecutive cases in
which the technique known as "no touch"1 was
used (with a guidewire in the aorta preventing the
guide catheter from dislodging aortic plaque), I
have not seen amputation, limb ischemia, or any
evident embolization.’
NEJM 2010;362:762
Criticisms of ASTRAL
5. Were the right patients enrolled?
‘The primary outcome was the change in renal function,
inferred from the reciprocal of the serum level of
creatinine. However, serum creatinine is only a rough
indicator of the glomerular filtration rate. Furthermore,
patients with major indications for revascularization were
excluded from the study, whereas patients with either
insignificant vascular lesions or advanced renal disease
(kidneys 6 cm in length), for whom no benefit from
revascularization could be expected, were enrolled.
Moreover, intraparenchymal resistance, a relevant
predictor of the success of revascularization, was not
evaluated.’
NEJM 2010;362:762
Criticisms of ASTRAL
6. Were the patients on the right drugs?
‘only about 40 to 50% of the patients were treated
with drugs that block the pathway of the renin–
angiotensin–aldosterone system; the use of such
drugs is currently recommended in any patient with
atherosclerotic renal-artery stenosis.’
NEJM 2010;362:762
Criticisms of ASTRAL
7. Severe RAS was not confirmed prior to entry
into the study
‘A major limitation of the ASTRAL trial was its
inclusion of patients whose diagnosis of renal artery
stenosis was made on the basis of noninvasive
imaging alone. No attempt was made to confirm the
severity of stenosis with digital subtraction
angiography or to assess its functional significance
before randomization.’
NEJM 2010;362:762
Criticisms of ASTRAL
8. Not all patients in the intervention group had
stenting
‘Furthermore, 17% of the patients in the
revascularization group did not proceed to
revascularization after invasive angiography.’
NEJM 2010;362:762
“be actuated by that perfect impartiality, which has
ever been considered most favorable to correct
decisions.”
Abraham Lincoln
Circulation 2007;115;263-270
Circulation 2007;115;271-276
• NIH Funded Trial
• Prospective, multi-center, two armed, randomized,
unblinded survival (time to event) clinical trial
• To test the hypothesis that optimal medical therapy +
stenting reduces the incidence of cardiovascular and renal
events compared to optimal medical therapy alone in
patients with systolic hypertension
• >100 centers participating
• 1080 patients
Documented history of
systolic hypertension
(>155 mm Hg) on 2 or
more antihypertensive
medications
 One or more renal artery
stenosis (> 60% stenosis)
 All patients receive OMT
- Randomization to stent vs
no stent
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Large and with long term follow-up
Clinically important outcomes
– Cardiovascular or Renal Death
– Stroke
– Myocardial Infarction
– Hospitalization from CHF
– Progressive Renal Insufficiency
– Renal Replacement Therapy
All patients receive ‘optimal medical
therapy’
Where do we stand now?
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In the absence of trials showing benefit from
revascularisation over conventional therapy and the
significant risk of complications it seems reasonable to
restrict procedures to patients who fail medical therapy
with:
– resistant or poorly-controlled hypertension
– recurrent flash pulmonary edema
– dialysis-dependent kidney failure resulting from renal artery
stenosis
– chronic renal insufficiency and bilateral renal artery stenosis
– renal artery stenosis to a solitary functioning kidney.
Agency for Healthcare Research and Quality (AHRQ)
Available at www.guideline.gov
Where do we stand now?
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In the absence of significant differences in long-term
outcome measures, given the rates of restenosis following
simple balloon angioplasty and the complications and
costs of surgical intervention, it would seem reasonable to
consider angioplasty with stenting as the revascularisation
procedure of choice for medically recalcitrant renal artery
stenosis. (Level IV evidence)
The above clinical guidelines refer to patients with
significant de novo renal artery stenosis (generally more
than 50%–80% reduction in luminal diameter). There have
been no studies in patients identified with lesser degrees
of stenosis. It seems reasonable to offer medical therapy in
these individuals, given the natural history of progressive
stenosis in atherosclerotic renal disease.
Agency for Healthcare Research and Quality (AHRQ)
Available at www.guideline.gov
Are we asking the wrong question?
Does RAS contribute to progression of vascular
disease?
 Are there different phases of RAS with potentially
different treatments?
 Will optimal treatment differ based on patient
characteristics?
 What constitutes optimal medical therapy?
 What outcomes should we measure?
 Is the disease more than just BP and Ang II?
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Data from Animal Model of
Renal Artery Stenosis
Ischemic damage
to ipsilateral
kidney
Unilateral RAS
Activation of
renin/Ang system
Damage to
contralateral
kidney
Time
CKD
Summary
RAS is an unusual cause of hypertension but a
common finding in patients with vascular disease
 RAS identifies patients with very poor prognosis
and a high risk of cardiovascular events
 Revascularization will benefit select patients with
RAS but convincing evidence of improved
cardiovascular outcomes in most patients is lacking
 A better understanding of the pathophysiology of
RAS is needed in order to design more effective
therapies
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RAS – Still much to learn!