UC UC SF SF Disclosures CORAL Trial: None Answers or More - - PowerPoint PPT Presentation

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CORAL Trial: Answers or More Questions?

Jade S. Hiramoto MD, MAS April 4, 2014 UCSF Vascular Symposium

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Disclosures

• None

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Atherosclerotic Renovascular Disease (ARVD)

• Well-known cause of hypertension, renal

insufficiency, ESRD

• Most common cause of secondary HTN, accounting

for 1-5% of all cases

• Commonly encountered
• ~7% of patients over 65 years old
• Incidental finding during imaging for other diseases or
• ther vascular interventions

– 20-45% of patients with CAD or aortoiliac disease

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Atherosclerotic Renovascular Disease (ARVD)

• Many treatment options have been applied:
• Medical therapy
• Renal artery angioplasty/stenting (RAS)
• Open surgical revascularization
• Published data, patient selection, choice of
• utcomes inconsistent across techniques

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Renal Artery Stenting (RAS)

• General consensus that renal

revascularization should be performed

• Flash pulmonary edema
• Acute kidney failure
• Many clinicians feel that patients with

multidrug-resistant HTN or deteriorating renal function should be treated

• Little evidence to support this

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Renal Artery Stent vs Medical Therapy: Randomized Trials

• Nephropathy Ischemic ThERapy (NITER)
• Renal Atherosclerotic reVascularization Evaluation

(RAVE)

• A RAndomised, multi-centre, prospective study

comparing best medical treatment versus best medical treatment plus renal artery stenting in patients with haemoDynamically relevant atherosclerotic renal ARtery stenosis (RADAR)

• Benefit of STent placement and blood pressure and

lipid-lowering for the prevention and progression of renal dysfunction caused by Athersclerotic ostial stenosis of the Renal artery (STAR)

• Angioplasty and STent for Renal Artery Lesions

(ASTRAL)

• Cardiovascular Outcomes in Renal Atherosclerotic

Lesions (CORAL)

No available results

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STAR

• Randomized clinical trial
• Efficacy and safety of stent placement in

patients with renal stenosis and impaired renal function

• 140 patients with stenosis > 50% and

eGFR<80 mL/min per 1.73m2

• Primary end point: 20% or greater

decrease in creatinine clearance

• Treatment arms:
• Medical treatment: antihypertensive, statin,

ASA (n=76)

• Stent placement and medical treatment

(n=64)

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STAR: Results

• Primary endpoint reached:
• 10/64 (16%) in stent group
• 16/76 (22%) in medication group
• HR 0.73, 95% CI 0.33-1.61
• 4 serious complications in stent group
• 2 procedure-related deaths
• 1 late death secondary to infected hematoma
• 1 required dialysis secondary to cholesterol embolism
• Conclusions:
• Stent placement: no clear effect on progression of

impaired renal function but was associated with severe procedure-related complications

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STAR: Limitations

• All patients required to have treated blood

pressure <140/90 on entry

• 46/140 (33%) had stenosis <70%
• Only 46/64 patients in stent group actually

received stent

• 12 pts had stenosis <50%
• Likely patients in medical group with <50% stenosis
• Study underpowered to provide definitive

estimate of efficacy

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Angioplasty and Stenting for Renal Artery Lesions (ASTRAL)

• Multicenter, randomized, unblinded trial
• Revascularization with medical therapy
• Medical therapy alone
• Primary endpoint:
• Rate of change of renal function over time
• Secondary endpoints:
• Blood pressure control
• CV and renal events
• Mortality

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ASTRAL: Patient Enrollment

• Participant eligibility:
• Substantial atherosclerotic stenosis in at

least one renal artery suitable for endovascular therapy AND

• The patient’s doctor was uncertain that the

patient would definitely have worthwhile clinical benefit from revascularization

• Not eligible:
• Required surgical revascularization
• High likelihood of requiring revascularization

within 6 months

• Previous revascularization for ARVD

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ASTRAL: Results

• 806 patients enrolled at 57 hospitals
• 59% had >70% stenosis
• 60% had serum creatinine of > 1.7mg/dL
• Revascularization was technically

successful in 317/403 (79%)

• 95% received a stent
• 24 patients (6%) in medical group

crossed over to revascularization

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ASTRAL: Results

• Over 5-years, rate of progression of renal

impairment favored revascularization group (p=0.06)

• Mean serum creatinine was 0.02 mg/dL lower

in revascularization group (p=0.06)

• No difference in SBP, renal events, major

CV events, and death

• 31 complications in 23 patients in

revascularization group

• 2 deaths
• 3 amputations of toes or limbs

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ASTRAL Investigators: Conclusions

• Substantial risks but no evidence of

worthwhile clinical benefit from revascularization in patients with ARVD

• However, similar to STAR…findings of

study in harmony with clinical experience

• Majority of study patients would not have

undergone stent placement

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ASTRAL: Limitations

• Over 40% of patients had < 70% stenosis
• No core laboratories to validate on-site stenosis

measurements

• Primary endpoint was rate of decline in renal

function

• 25% of enrolled patients had normal renal function

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CORAL Trial: Background

• Atherosclerotic renal artery stenosis is

common problem

• Two randomized trials did not show

benefit of renal artery stenting with respect to kidney function

• Usefulness of renal stent placement for

prevention of major adverse renal and CV events is uncertain

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CORAL Trial

• Hypothesis: Optimal medical therapy with RAS in

patients with systolic HTN reduces incidence of adverse CV and renal events

• Primary entry criteria:
• All patients will undergo renal angiography
• Stenosis >60% with 20mmHg pressure gradient or

>80% with no gradient

• Systolic HTN > 155mmHg on > 2 antihypertensive

medications

• Randomize to medical therapy alone vs RAS with

medical therapy

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CORAL Trial: Interventions

• Medical therapy alone
• Candesartan (angiotensin receptor blocker) ±

hydrochlorthiazide

• Amlodipine-atorvastatin
• Doses adjusted based on blood pressure and lipid status
• Target BP: <140/90 in patients without coexisting

conditions and <130/80 in patients with diabetes or CKD

• Stenting plus medical therapy
• Palmaz Genesis stent
• Prior to 8/2006: short-tip Angioguard used for embolic

protection

• After 8/2006: any FDA-approved embolic protection

device could be used

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Overall Design of the CORAL Trial

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CORAL Trial: Endpoints

• Primary endpoint: Major CV or renal event
• CV or renal death
• MI
• CHF
• Stroke
• Progressive renal insufficiency
• Need for renal replacement therapy
• Secondary endpoints:
• All-cause mortality
• Individual components of the primary end point

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What Were We Supposed to Learn From CORAL?

• The effect of revascularization for

hemodynamically significant renal artery stenosis in hypertensive patients on:

• Prevention of adverse CV and renal events when

added upon background of optimal medical therapy

• Blood pressure control
• Prevention of renal dysfunction

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CORAL Trial: Reality

• Several changes made during course of trial

based on slow recruitment:

• Threshold of 155 mmHg for defining HTN no longer

specified

• Could enroll patients without hypertension if they had

chronic kidney disease (eGFR<60ml/min/1.73m2)

• Severe renal artery stenosis could be identified with

duplex ultrasound, magnetic resonance angiography,

• r computed tomographic angiography
• All renal arteries with stenoses of ≥60% were treated

(gradient no longer required)

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CORAL Trial: Results

• Between 5/2005-1/2010, 5322 patients were

screened, 947 patients randomized

• Medical therapy alone (n=480)
• Stenting plus medical therapy (n=467)
• Data from 16 patients excluded secondary to scientific

integrity

• 19 patients in medical therapy group crossed over to

stenting

• Median follow-up of 43 months (IQR: 31 to 55)

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Coral Trial: Results

Cooper et al; NEJM 2014

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CORAL Trial: Results

Cooper et al; NEJM 2014

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CORAL Trial: Results

Cooper et al; NEJM 2014

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CORAL Trial: Results

Cooper et al; NEJM 2014

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CORAL Trial: Blood Pressure Over Time

• At baseline, participants taking a mean of 2.1±1.6

antihypertensive medications

• Number of meds increased in both groups (3.3

±1.5 in stent group, 3.5 ±1.4 meds in medical Rx group; p=0.24)

• SBP declined in both medical Rx group (by 15.6

± 25.8 mmHg) and stent group (by 16.6 ± 21.2 mmHg)

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CORAL Trial: Blood Pressure Over Time

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CORAL Trial: Conclusions

• Stent implantation for ARVD is no better than

high-quality medical therapy alone in patients with:

• ≥ 60% renal artery stenosis AND
• Hypertension on ≥ 2 medications OR stage 3 CKD
• Findings applicable to those patients with

uncertain lesions where there is equipoise for randomization into clinical trial

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CORAL Trial: Limitations

• Patients could be enrolled with renal artery

stenosis ≥ 60%

• Debate as to whether this is severe enough to justify

intervention

• Inability to select hemodynamically severe renal

artery stenoses for treatment

• No pressure gradient measured
• Difficult to separate true renovascular hypertension from

those with ARVD and essential hypertension

• Many screen-eligible patients were not enrolled

because of physician preference

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CORAL Trial: Caveats

• Can the medical therapy in this trial be

replicated in clinical practice?

• ARB +/- thiazide diuretic
• Amlodipine for additional BP control
• Antiplatelet therapy
• Atorvastatin for management of lipid levels
• Diabetes managed according to clinical

practice guidelines

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CORAL and Clinical Practice

• Patients with presumed atherosclerotic

renovascular hypertension:

• Should be given trial of multifactorial medical therapy to

lower blood pressure

• However…
• In those patients with >70% stenosis and poorly

controlled blood pressure on ≥ 3 drugs, reasonable to offer renal artery stenting

• American College of Cardiology and American

Heart Association guidelines document

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CORAL Trial: Answers or More Questions?

• I think it has answered the “middle ground”

question

• A couple more questions…
• Is renal artery stenting + medical therapy

effective treatment in patients with poorly controlled blood pressure despite multifactorial medical therapy?

• Is there benefit in those with renal artery stenosis

hemodynamically confirmed as a cause of renovascular ischemia?