stouffer ras
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Renal Artery Stenosis – The Good,The Bad and The Different
Rick Stouffer MD
University of North Carolina
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Disclosure
I will discuss off-label uses No financial conflicts of interest
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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
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Renal artery revascularization
• Accelerated HTN• Mild elevation in
creatinine
• Symptoms
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Did We Benefit This Patient?
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Outline
Types of RAS Atherosclerotic RAS
Natural history of the patient with RAS
Treatment of RAS
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Renal Artery Stenosis
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
Aortorenal dissection
Vasculitis involving the renal artery (i.e. PAN)
AVMs involving the renal artery Irradiation of the renal artery
Scleroderma
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FMD – Anatomy and Pathophysiology
70 year old female with chest pain
and 4-drug hypertension.
Circulation. 2005;112:e278-9.
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Before balloon angioplasty After balloon angioplasty
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A Cautionary Tale 37-year-old male admitted with headache of six
months duration that had worsened in the last wee
and was accompanied by blurry vision, dyspnea onexertion and weakness in his legs.
No significant PMH, was not taking anymedications 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 significan
difference between arms.
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A Cautionary Tale BP = 252/160 mm Hg Ophthamology consultant - Grade IV retinopathy
including marked AV nicking and venous dilatationcotton wool spots, large areas of choroidalischemia, delayed vascular filling, blind spots andpapilledema in both eyes.
MRI of the brain - No evidence of intracerebralmass but increased signal abnormality within thepons, consistent with hypertensive encephalopathy
MRI/MRA of the abdomen showed normal kidney
size, no renal or adrenal masses and „No evidenceof 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.
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5 years later - He has run marathons and climbed Mount
Kilimanjaro. Home systolic BPs of 130 mm Hg on HCTZ 20 mgdaily, enalapril 10 mg daily and Norvasc 10 mg twice daily.
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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
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Prevalence of Atherosclerotic RAS
Unselected autopsies 4-27% Hypertensives 1-4% Aged 65 years and older 6.8% Diabetics 8%
– 6.8% in healthy adults > 65 years old
– Evaluation with renal artery duplex of 834 patients consecutive patientswho were participants in the Forsyth county cohort of the CardiovascularHealth Study ( J Vasc Surg. 2002;36:443 – 51).
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RAS is common in patientswith vascular disease
Prevalence of RAS – Proven MI 12%
– Undergoing cardiac catheterization 6-19%
– Lower extremity PVD 22-59%
Predictors of RAS in patients undergoing cardiaccatheterization
– CAD; Age; PVD; serum creatinine; hypertension
T diti l P di f
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Traditional Paradigm ofRenal Artery Stenosis
Renal Angio(anatomic)
Revascularization
Severe HTN
Physiologictesting for RAS
Th Ch i P di f
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The Changing Paradigm ofRenal Artery Stenosis
Renal Angio(anatomic)
Revascularization
Severe HTN
Physiologictesting for RAS
Evaluation forVascular Disease
(usually CAD)
Chest pain,dyspnea, etc
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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
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RAS is a marker of a poor prognosis
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Dismal Prognosis Associated with RAS
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)
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 percutaneousrenal revascularization (Circulation 1998;98:642-647)
5 year mortality – 33% in a single-center study of patients undergoing percutaneourenal artery revascularization (Catheter Cardiovasc Interv . 2007;69:1037)
Effect of RAS on Prognosis
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Ries LAG et al. SEER Cancer Statistics Review, 1973-1998.
National Cancer Institute. September 2000.
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80
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RASBreastCancer
ColorectalCancer
Non-HodgkinsLymphoma
Effect of RAS on Prognosis –
Relative Five year Survival
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Clinical Events in Patients With RAS
J Am Coll Cardiol Intv 2009;2:175-182
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.
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The $64000 Question
Is RAS a marker of severe atherosclerosis and thuportends a poor prognosis?
or
Does RAS contribute to progression of vasculardisease - thus implying that effective treatment mayimprove clinical outcomes?
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Outline
Types of RAS Atherosclerotic RAS
Natural history of the patient with RAS
Treatment of RAS
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Optimal Medical Treatment
ARB + diuretic to get BP totarget – <140/90 mm Hg
– <130/80 mm Hg with DM
LDL to goal – Currently <100 (or 70) mg/dl
Diabetes Management – HbA1c to target (<7%)
Smoking Cessation Anti-platelet therapy (aspirin
+/- clopidogrel/prasugrel)
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What role does revascularization play?
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Percutaneous Treatment of RAS
1978 - Gruentzig and colleagues report first balloonangioplasty of renal artery stenosis – Gruentzig A, Kuhlmann U, Vetter W. Treatment of renovascular
hypertension with percutaneous transluminal dilatation of a renalartery stenosis. Lancet 1978; 1:801-802.
Fall 1978 - first renal artery angioplasty in US at UVa. -Patient referred by Carlos Ayers to Charles Tegtmeyerwho obtained angioplasty balloon from Gruentzig inexchange for fishing equipment. – Tegtmeyer CJ, Dyer R, Teates CD, Ayers CR, Carey RM,
Wellons HA Jr, Stanton LW. Percutaneous transluminal dilatationof the renal arteries: techniques and results. Radiology 1980;135(3);589-599
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Treatment of RAS
Surgery
PTRA
Stents
EP
1950 1960 1970 1980 1990 2000 2010
Surgery
PTRA
Stents
EP
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Evidence-based Medicine
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Evidence-based Medicine
Reviewed 55 studies “Almost two thirds of the studies that we reviewed were of
poor methodologic quality; none was deemed to be ofgood quality.”
“More than half of the studies had limited applicability topatients commonly seen in practice or to modernmanagement strategies.”
“No study directly compared angioplasty with stent
placement and "aggressive" medical treatment withcurrently available antihypertensive, antiplatelet, and lipid-lowering agents.”
Eff t f RA R l i ti HTN
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Effect of RA Revascularization on HTN
Study Device N Cure Improved
Klinge stent 134 10% 68%
Lossino stent 153 12% 51%
DRASTIC balloon 106 7% 68% Rocha stent 150 6% 50%
Dorros stent 145 1% 52%
Effects of RA Revascularization on Ischemic
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Effects of RA Revascularization on IschemicNephropathy
Prog Cardiovasc Dis 2007;50:13
Angioplasty and STent for
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Angioplasty and STent for
Renal Artery Lesions
NEJM 2009;361:1953-1962
ASTRAL Trial
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Substantial atherosclerotic RAS
Suitable for endovascular revascularization
Patient's doctor was uncertain that the patient would
benefit from revascularization
No revascularisation
(n = 403) Medical treatment according to
local protocol
Revascularisation
(n = 403)
with angioplasty and/or stent
(and medical treatment)
PATIENT CHARACTERISTICS
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PATIENT CHARACTERISTICS
Revasc. Medical P-valueMean age (range) 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
(5.4 – 124.5)
39.8
(7.1 – 121.7)
0.7
Blood Press re Cholesterol Stenosis
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Blood Pressure, Cholesterol, Stenosis
Procedural Complications
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Procedural Complications
38 periprocedural complications in 31 of the 359 patients(9%) who underwent revascularization (including 1 of the24 patients in the medical-therapy group who crossed oveto 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 Renal-artery perforations (4)
– Femoral-artery aneurysm (1)
– Cholesterol embolism leading to peripheral gangrene andamputation of toes or limbs (3)
Medications at One Year
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Medications at One Year
Revasc. Medical P-valu
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
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Blood Pressure
Serum Creatinine
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Serum Creatinine
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Clinical Events
Survival
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Survival
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• “An important limitation of our trial concerns the population that westudied. 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) – 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
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answered?
Criticisms of ASTRAL
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Criticisms of ASTRAL
1. Selection bias and inexperienced operators „On average, 2 patients per center per year underwent
randomization, which indicates serious selection bias orinexperienced staff at centers with very low intervention
rates. This concern is supported by a low rate of technicalsuccess (317 of 403 patients [79%] in the revascularizatiogroup) and a high rate of serious complication in 23 of 280patients (8%) as compared with reports in the literature of
98% and 2%, respectively.‟
NEJM 2010;362:762
Criticisms of ASTRAL
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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 wa
used to achieve normalized blood pressure in both groupsThus, not only the blood pressure values but also thenumber of antihypertensive drugs used to achieve thisgoal should be taken into account. The … significantly
lower number of antihypertensive drugs administered inthe revascularization group (P=0.03) preclude the
definitive conclusion that renal-artery revascularizationprovides no clinical benefit.‟
NEJM 2010;362:762
Criticisms of ASTRAL
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Criticisms of ASTRAL
3. Patients with severe RAS were not enrolled
„The results of the ASTRAL investigation should be readand interpreted critically. As with the COURAGE (ClinicalOutcomes Utilizing Revascularization and AggressiveDrug Evaluation) trial, the take-home message should bethat for patients with a moderate degree of renal-artery
stenosis, medical management is as effective asrevascularization over a 5-year follow-up period. Patientsseen as requiring anatomical correction were not enrolledonly those deemed suitable for randomization to stentingor medical therapy were included. Thus, the patients most
likely to benefit from stenting (those with subocclusivelesions or with very severe disease in one or both kidneyswere not part of this study.‟
NEJM 2010;362:762
Criticisms of ASTRAL
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Criticisms of ASTRAL
4. More concern about high complication rate
„Another concern is the prohibitively high rate ofamputation and embolization in this study. Thiscalls into question the appropriateness and safetyof the techniques currently used to perform theprocedure. In more than 200 consecutive cases inwhich the technique known as "no touch"1 wasused (with a guidewire in the aorta preventing theguide catheter from dislodging aortic plaque), Ihave not seen amputation, limb ischemia, or anyevident embolization.‟ NEJM 2010;362:762
Criticisms of ASTRAL
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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 ofcreatinine. However, serum creatinine is only a roughindicator of the glomerular filtration rate. Furthermore,patients with major indications for revascularization were
excluded from the study, whereas patients with eitherinsignificant vascular lesions or advanced renal disease(kidneys 6 cm in length), for whom no benefit fromrevascularization could be expected, were enrolled.Moreover, intraparenchymal resistance, a relevant
predictor of the success of revascularization, was notevaluated.‟
NEJM 2010;362:762
Criticisms of ASTRAL
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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 withatherosclerotic renal-artery stenosis.‟
NEJM 2010;362:762
Criticisms of ASTRAL
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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 arter
stenosis was made on the basis of noninvasiveimaging alone. No attempt was made to confirm theseverity of stenosis with digital subtractionangiography or to assess its functional significancebefore randomization.‟
NEJM 2010;362:762
Criticisms of ASTRAL
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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
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y p p y,
ever been considered most favorable to correct
decisions.”
Abraham Lincoln
Circulation 2007;115;271-276Circulation 2007;115;263-270
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• 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 rena
events compared to optimal medical therapy alone in
patients with systolic hypertension
• >100 centers participating
• 1080 patients
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Documented history ofsystolic hypertension(>155 mm Hg) on 2 ormore antihypertensive
medications One or more renal arterystenosis (> 60% stenosis)
All patients receive OMT
- Randomization to stent vsno stent
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 medica
therapy‟
Where do we stand now?
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In the absence of trials showing benefit from
revascularisation over conventional therapy and thesignificant risk of complications it seems reasonable torestrict procedures to patients who fail medical therapywith: – resistant or poorly-controlled hypertension
– recurrent flash pulmonary edema – dialysis-dependent kidney failure resulting from renal arterystenosis
– 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-termoutcome measures, given the rates of restenosis following
simple balloon angioplasty and the complications andcosts of surgical intervention, it would seem reasonable toconsider angioplasty with stenting as the revascularisationprocedure of choice for medically recalcitrant renal arterystenosis. (Level IV evidence)
The above clinical guidelines refer to patients withsignificant de novo renal artery stenosis (generally morethan 50% –80% reduction in luminal diameter). There havebeen no studies in patients identified with lesser degreesof stenosis. It seems reasonable to offer medical therapyin these individuals, given the natural history ofprogressive stenosis in atherosclerotic renal disease.
Agency for Healthcare Research and Quality (AHRQ
Available at www.guideline.gov
Are we asking the wrong question?
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Does RAS contribute to progression of vasculardisease?
Are there different phases of RAS with potentiallydifferent treatments?
Will optimal treatment differ based on patientcharacteristics?
What constitutes optimal medical therapy?
What outcomes should we measure? Is the disease more than just BP and Ang II?
Data from Animal Model ofRenal Artery Stenosis
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Renal Artery Stenosis
Activation ofrenin/Ang system
CKD
Unilateral RAS
Ischemic damageto ipsilateral
kidney
Damage tocontralateral
kidney
Time
Summary
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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 withRAS but convincing evidence of improvedcardiovascular outcomes in most patients is lacking
A better understanding of the pathophysiology of
RAS is needed in order to design more effectivetherapies
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RAS – Still much to learn!
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