UC UC SF SF Disclosures CORAL Trial: • None Answers or More Questions? Jade S. Hiramoto MD, MAS April 4, 2014 UCSF Vascular Symposium VASCULAR SURGERY • UC SAN FRANCISCO VASCULAR SURGERY • UC SAN FRANCISCO UC UC SF SF Atherosclerotic Renovascular Atherosclerotic Renovascular Disease (ARVD) Disease (ARVD) • Well-known cause of hypertension, renal • Many treatment options have been applied: insufficiency, ESRD - Medical therapy - Most common cause of secondary HTN, accounting - Renal artery angioplasty/stenting (RAS) for 1-5% of all cases - Open surgical revascularization • Commonly encountered • Published data, patient selection, choice of - ~7% of patients over 65 years old outcomes inconsistent across techniques - Incidental finding during imaging for other diseases or other vascular interventions – 20-45% of patients with CAD or aortoiliac disease VASCULAR SURGERY • UC SAN FRANCISCO VASCULAR SURGERY • UC SAN FRANCISCO 1
UC UC SF SF Renal Artery Stent vs Medical Therapy: Renal Artery Stenting (RAS) Randomized Trials • Nephropathy Ischemic ThERapy (NITER) • General consensus that renal • Renal Atherosclerotic reVascularization Evaluation revascularization should be performed (RAVE) • A RAndomised, multi-centre, prospective study - Flash pulmonary edema comparing best medical treatment versus best medical No - Acute kidney failure available treatment plus renal artery stenting in patients with results haemoDynamically relevant atherosclerotic renal ARtery stenosis (RADAR) • Many clinicians feel that patients with multidrug-resistant HTN or deteriorating renal • Benefit of STent placement and blood pressure and function should be treated lipid-lowering for the prevention and progression of renal dysfunction caused by Athersclerotic ostial - Little evidence to support this stenosis of the Renal artery (STAR) • Angioplasty and STent for Renal Artery Lesions (ASTRAL) • Cardiovascular Outcomes in Renal Atherosclerotic Lesions (CORAL) VASCULAR SURGERY • UC SAN FRANCISCO VASCULAR SURGERY • UC SAN FRANCISCO UC UC SF SF STAR STAR: Results • Randomized clinical trial • Primary endpoint reached: - 10/64 (16%) in stent group - Efficacy and safety of stent placement in - 16/76 (22%) in medication group patients with renal stenosis and impaired - HR 0.73, 95% CI 0.33-1.61 renal function • 140 patients with stenosis > 50% and • 4 serious complications in stent group eGFR<80 mL/min per 1.73m 2 - 2 procedure-related deaths • Primary end point: 20% or greater - 1 late death secondary to infected hematoma decrease in creatinine clearance - 1 required dialysis secondary to cholesterol embolism • Treatment arms: - Medical treatment: antihypertensive, statin, • Conclusions: ASA (n=76) - Stent placement: no clear effect on progression of impaired renal function but was associated with - Stent placement and medical treatment severe procedure-related complications (n=64) VASCULAR SURGERY • UC SAN FRANCISCO VASCULAR SURGERY • UC SAN FRANCISCO 2
UC UC SF SF Angioplasty and Stenting for STAR: Limitations Renal Artery Lesions (ASTRAL) • All patients required to have treated blood • Multicenter, randomized, unblinded trial pressure <140/90 on entry - Revascularization with medical therapy - Medical therapy alone • 46/140 (33%) had stenosis <70% • Primary endpoint: • Only 46/64 patients in stent group actually - Rate of change of renal function over time received stent - 12 pts had stenosis <50% - Likely patients in medical group with <50% stenosis • Secondary endpoints: - Blood pressure control • Study underpowered to provide definitive - CV and renal events estimate of efficacy - Mortality VASCULAR SURGERY • UC SAN FRANCISCO VASCULAR SURGERY • UC SAN FRANCISCO UC UC SF SF ASTRAL: Results ASTRAL: Patient Enrollment • 806 patients enrolled at 57 hospitals • Participant eligibility: - 59% had >70% stenosis - Substantial atherosclerotic stenosis in at - The patient ’ s doctor was uncertain that the least one renal artery suitable for - 60% had serum creatinine of > 1.7mg/dL endovascular therapy AND patient would definitely have worthwhile • Revascularization was technically clinical benefit from revascularization successful in 317/403 (79%) - 95% received a stent • Not eligible: - Required surgical revascularization - High likelihood of requiring revascularization • 24 patients (6%) in medical group within 6 months crossed over to revascularization - Previous revascularization for ARVD VASCULAR SURGERY • UC SAN FRANCISCO VASCULAR SURGERY • UC SAN FRANCISCO 3
UC UC ASTRAL: Results SF SF ASTRAL Investigators: Conclusions • Over 5-years, rate of progression of renal impairment favored revascularization group (p=0.06) • Substantial risks but no evidence of - Mean serum creatinine was 0.02 mg/dL lower worthwhile clinical benefit from in revascularization group (p=0.06) revascularization in patients with ARVD • No difference in SBP, renal events, major CV events, and death • However, similar to STAR…findings of study in harmony with clinical experience • 31 complications in 23 patients in - Majority of study patients would not have revascularization group undergone stent placement - 2 deaths - 3 amputations of toes or limbs VASCULAR SURGERY • UC SAN FRANCISCO VASCULAR SURGERY • UC SAN FRANCISCO UC UC SF SF ASTRAL: Limitations CORAL Trial: Background • Atherosclerotic renal artery stenosis is • Over 40% of patients had < 70% stenosis common problem • No core laboratories to validate on-site stenosis measurements • Two randomized trials did not show benefit of renal artery stenting with • Primary endpoint was rate of decline in renal respect to kidney function function - 25% of enrolled patients had normal renal function • Usefulness of renal stent placement for prevention of major adverse renal and CV events is uncertain VASCULAR SURGERY • UC SAN FRANCISCO VASCULAR SURGERY • UC SAN FRANCISCO 4
UC UC CORAL Trial: Interventions SF SF CORAL Trial - Candesartan (angiotensin receptor blocker) ± • Medical therapy alone • Hypothesis: Optimal medical therapy with RAS in hydrochlorthiazide patients with systolic HTN reduces incidence of - Amlodipine-atorvastatin adverse CV and renal events - Doses adjusted based on blood pressure and lipid status • Primary entry criteria: - Target BP: <140/90 in patients without coexisting conditions and <130/80 in patients with diabetes or CKD - All patients will undergo renal angiography - Stenosis >60% with 20mmHg pressure gradient or >80% with no gradient • Stenting plus medical therapy - Systolic HTN > 155mmHg on > 2 antihypertensive medications - Palmaz Genesis stent - Prior to 8/2006: short-tip Angioguard used for embolic • Randomize to medical therapy alone vs RAS with protection medical therapy - After 8/2006: any FDA-approved embolic protection device could be used VASCULAR SURGERY • UC SAN FRANCISCO VASCULAR SURGERY • UC SAN FRANCISCO UC UC SF SF Overall Design of the CORAL Trial 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 VASCULAR SURGERY • UC SAN FRANCISCO VASCULAR SURGERY • UC SAN FRANCISCO 5
UC UC SF SF What Were We Supposed to CORAL Trial: Reality Learn From CORAL? • Several changes made during course of trial • The effect of revascularization for based on slow recruitment: hemodynamically significant renal artery stenosis in hypertensive patients on: - Threshold of 155 mmHg for defining HTN no longer specified - Prevention of adverse CV and renal events when - Could enroll patients without hypertension if they had added upon background of optimal medical therapy chronic kidney disease (eGFR<60ml/min/1.73m 2 ) - Severe renal artery stenosis could be identified with - Blood pressure control duplex ultrasound, magnetic resonance angiography, or computed tomographic angiography - All renal arteries with stenoses of ≥ 60% were treated - Prevention of renal dysfunction (gradient no longer required) VASCULAR SURGERY • UC SAN FRANCISCO VASCULAR SURGERY • UC SAN FRANCISCO UC UC SF SF CORAL Trial: Results • Between 5/2005-1/2010, 5322 patients were screened, 947 patients randomized Coral Trial: - Medical therapy alone (n=480) Results - 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) VASCULAR SURGERY • UC SAN FRANCISCO Cooper et al; NEJM 2014 VASCULAR SURGERY • UC SAN FRANCISCO 6
UC UC CORAL Trial: Results SF SF CORAL Trial: Results VASCULAR SURGERY • UC SAN FRANCISCO VASCULAR SURGERY • UC SAN FRANCISCO Cooper et al; NEJM 2014 Cooper et al; NEJM 2014 UC UC CORAL Trial: Results SF SF CORAL Trial: Blood Pressure Over Time • At baseline, participants taking a mean of 2.1 ± 1.6 antihypertensive medications ± 1.5 in stent group, 3.5 ± 1.4 meds in medical Rx • Number of meds increased in both groups (3.3 group; p=0.24) ± 25.8 mmHg) and stent group (by 16.6 ± 21.2 • SBP declined in both medical Rx group (by 15.6 mmHg) VASCULAR SURGERY • UC SAN FRANCISCO VASCULAR SURGERY • UC SAN FRANCISCO Cooper et al; NEJM 2014 7
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