Stouffer RAS

8/12/2019 Stouffer RAS

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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



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



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



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 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.



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.‟



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 mgdaily, enalapril 10 mg daily and Norvasc 10 mg twice daily.



Outline



Treatment of RAS



Atherosclerotic RAS

• Usually ostial• Associated with diseased

aorta

• Can be unilateral or bilateral



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).



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



Traditional Paradigm ofRenal Artery Stenosis

Renal Angio(anatomic)

Revascularization

Severe HTN

Physiologictesting for RAS

Th Ch i P di f



The Changing Paradigm ofRenal Artery Stenosis

Renal Angio(anatomic)

Revascularization

Severe HTN

Physiologictesting for RAS

Evaluation forVascular Disease

(usually CAD)

Chest pain,dyspnea, etc



Outline

Types of RAS Atherosclerotic RAS - Prevalence and 'Risk factors


Treatment of RAS



A tale of two patients



RAS is a marker of a poor prognosis



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



Ries LAG et al. SEER Cancer Statistics Review, 1973-1998.

National Cancer Institute. September 2000.

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20

40

60

80

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RASBreastCancer

ColorectalCancer

Non-HodgkinsLymphoma

Effect of RAS on Prognosis –

Relative Five year Survival



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.



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?



Outline



Treatment of RAS



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)



What role does revascularization play?



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



Treatment of RAS

Surgery

PTRA

Stents

EP

1950 1960 1970 1980 1990 2000 2010

Surgery

PTRA

Stents

EP



Evidence-based Medicine



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



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



Effects of RA Revascularization on IschemicNephropathy

Prog Cardiovasc Dis 2007;50:13

Angioplasty and STent for



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

No revascularisation

(n = 403) Medical treatment according to

local protocol

Revascularisation

(n = 403)

with angioplasty and/or stent

(and medical treatment)

PATIENT CHARACTERISTICS



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



Blood Pressure, Cholesterol, Stenosis

Procedural Complications



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



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



Blood Pressure

Serum Creatinine

http://content.nejm.org/content/vol361/issue20/images/large/11f2.jpeg



Serum Creatinine




Clinical Events

Survival




Survival




• “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



answered?

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





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





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





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





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





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





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




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



y p p y,

ever been considered most favorable to correct

decisions.”

Abraham Lincoln

Circulation 2007;115;271-276Circulation 2007;115;263-270



• 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



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?



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?



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?



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



Renal Artery Stenosis

Activation ofrenin/Ang system

CKD

Unilateral RAS

Ischemic damageto ipsilateral

kidney

Damage tocontralateral

kidney

Time

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 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



RAS – Still much to learn!



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Stouffer RAS