Renal Artery Stenosis: Insights from the CORAL Trial Christopher J. Cooper, M.D., FACC, FACP Dean and Senior Vice President University of Toledo, College of Medicine President, Ohio Chapter ACC
State of Renal Stenting Observational studies suggest that stenting of renal artery stenosis improves blood pressure and stabilizes kidney function. It was assumed that: 1. These effects were due to the stent, and 2. Would result in better outcomes for patients.
Systolic Blood Pressure (mm Hg) Stenting and Blood Pressure 200 p<0.001 p<0.001 p<0.001 p<0.001 p<0.001 p=0.002 p=0.01 180 160 140 120 100 80 60 40 20 0 Baseline Post Procedure 1 Month 3 Month 6 Month 1 Year 2 Year 3 Year Am Heart J 2000;139:64-7.
Registries suggest renal artery stenting preserves renal function Medical therapy Associated with progressive decline in renal function Stenting Beneficial effect on slope of 1/Cr Stabilization Chabova Mayo Clin Proc 2000;75:437-44. Dean RH Arch Surg 1981;116:1408-1415. Harden Lancet 1997;349:1133-1136. Watson Circ 2000;102:1671-7.
Management of Atherosclerotic RAS Nephrectomy to correct hypertension Renal artery bypass surgery Excellent patency but high in hospital mortality Modrall 2009, Hansen & Dean 2002 Balloon angioplasty Low mortality but high restenosis Weibull 1993 Stenting Lower restenosis than balloon angioplasty van de Ven 1999
Reason we do randomized clinical trials: To test therapies or strategies that have moderate treatment effects. Meinert CL. Clinical trial, design, conduct and analysis. 1986.
UK MULTI-CENTRE TRIAL IN ATHEROSCLEROTIC RENOVASCULAR DISEASE ASTRAL Angioplasty and STent for Renal Artery Lesions Philip A Kalra Lead Nephrologist for ASTRAL, Hope Hospital, Salford, UK, On behalf of the ASTRAL TMC and collaborators
ASTRAL Trial 806 patients 1) with 1 ARVD lesion, and 2) in whom substantial uncertainty about whether early revascularization is clinically indicated. In particular it should be unlikely that revascularization will become definitely indicated within the next 6 months. 806 403 Medical Rx 403 Stent Assigned 308 Stent (76%) 44 Not Attempted 17 Failed 34 Not Known
ASTRAL: No Difference in Kidney function, BP or Events ASTRAL Investigators N Engl J Med 2009;361:1953-1962.
A Randomized Multicenter Clinical Trial of Renal Artery Stenting in Preventing Cardiovascular and Renal Events: Results of the CORAL Study Christopher J. Cooper, M.D., Timothy P. Murphy, M.D., Donald E. Cutlip, M.D., Kenneth Jamerson, M.D., William Henrich, M.D., Diane M. Reid, M.D., David J. Cohen, M.D., M.Sc., Alan H. Matsumoto, M.D., Michael Steffes, M.D., Michael R. Jaff, D.O., Martin R. Prince, M.D., Ph.D., Eldrin F. Lewis, M.D., Katherine R. Tuttle, M.D., Joseph I. Shapiro, M.D., M.P.H., John H. Rundback, M.D., Joseph M. Massaro, Ph.D., Ralph B. D Agostino, Sr., Ph.D., and Lance D. Dworkin, M.D. Available online at www.nejm.org on behalf of the CORAL Investigators
Methods Open label, randomized, international, multicenter controlled clinical trial Medical Therapy: BP, Diabetes and Lipids to goal Anti-platelet therapy Participants provided: Candesartan ± hydrochlorothiazide Atorvastatin + Amlodipine (Caduet ) C. Cooper, NEJM 2014
Inclusion Criteria Clinical Syndrome: Hypertension 2 anti-hypertensive medications, OR Renal dysfunction defined as Stage 3 or greater CKD -AND- Renal Artery Stenosis: Angiographic: 60% and < 100%, OR Duplex: systolic velocity of >300 cm/sec, OR Core lab approved MRA, OR Core lab approved CTA C. Cooper, NEJM 2014
Core Laboratories Angiography University of Virginia Duplex Ultrasound VasCore, Massachusetts General Hospital MRA + CTA Weill-Cornell Biochemistry University of Minnesota Clinical University of Toledo Data Harvard Clinical Research Institute C. Cooper, NEJM 2014
Statistical Plan 90% power to test hypothesis that stenting reduced the incidence of the primary endpoint by 25% C. Cooper, NEJM 2014
Baseline Characteristics Baseline Characteristics of the Study Population According to Treatment Group Approximately 20% global ischemia Stenosis severity similar to FDA approval trials 1-3 Characteristic Stent + Medical Medical N = 459 N = 472 Age (years) 69.3 ± 9.4 69.0 ± 9.0 Male gender (%) 51.0 48.9 White race (%) 91.5 90.9 Black race (%) Body mass index (kg/m 2 ) Systolic blood pressure (mmhg) Estimate GFR (ml/minute) 7.0 28.2 ± 5.3 149 ± 23.2 58.0 ± 23.4 7.0 28.7 ± 5.7 150.4 ± 23.0 57.4 ± 21.7 1. Rocha-Singh K et. al. ASPIRE-2. JACC 2005;46:776-83 2. Rocha-Singh K et. al. RENAISSANCE. CCI 2008;72:853-62 3. Jaff MR, et. al. HERCULES. CCI 2012;80:343-50 Medical history and risk factors (%) Diabetes Prior myocardial infarction History of heart failure Smoking in past year Angiography % stenosis (core lab) 32.4 34.3 26.5 30.2 12.0 15.1 28.0 32.2 67.3 ± 11.4 66.9 ± 11.9 % stenosis (investigator) 72.5 ± 14.6 74.3 ± 13.1 Global ischemia (%) 20.0 16.2 Bilateral disease (%) 22.0 18.1 Cooper CJ et al. NEJM 2014;370:13-22.
Results: Stent Treatment Angiographic Core Lab Analysis Stenosis from 68±11% to 16±8% (p<0.001). Stents per vessel 1.04±0.20 Embolic protection device, per vessel 124/543 (22.8%) Procedural complications Dissection 11/495 (2.2%) Branch vessel occlusion 6/495 (1.2%) Angiographic distal embolization 6/495 (1.2%) Wire perforation 1/495 (0.2%) Vessel rupture 1/495 (0.2%) Pseudoaneurysm 1/495 (0.2%) C. Cooper, NEJM 2014
Primary Endpoint First major cardiovascular or renal event, defined as a composite of: Cardiovascular or Renal Death Stroke MI CHF Hospitalization Progressive Renal Insufficiency Permanent Renal Replacement Therapy C. Cooper, NEJM 2014
Results: Primary Endpoint Stent plus medical therapy Medical therapy Stent + Medical Therapy 35.1% Medical Therapy 35.8% HR 0.94 [0.76-1.17], p =0.58 Cooper CJ et al. NEJM 2014;370:13-22.
Results: Secondary Endpoints CV + Renal Death Stroke Myocardial Infarction P=ns P=ns P=ns Heart Failure Progressive Renal Insufficiency Renal Replacement P=ns P=ns P=ns C. Cooper, NEJM 2014
WAIT! You just need to pick the patients better!!!
Results: Subgroups
But what about blood pressure, I know my patients BP gets better when they are stented!
Results: Systolic Blood Pressure P = 0.03 Cooper CJ et al. NEJM 2014;370:13-22.
What about the BP Effects of Stenting FDA approval trial of Herculink stent data published July 2014 Baseline systolic blood pressure of 162 mmhg decreased to 146 mmhg at 36 months, P<0.001. The systolic blood pressure reduction in the Medical Therapy Only arm of CORAL 15.6 mmhg!!! J Clinical Hypert 2014;16:497. NEJM 2014;370:13-22.
CORAL Conclusion: Renal artery stenting does not confer benefits for the prevention of clinical events, when added to medical therapy, in people with renal artery stenosis. Cooper CJ et al. NEJM 2014;370:13-22.
So when is Medical Therapy Preferred? Hypertension on medical therapy or CKD stage 3 with renal artery stenosis (CORAL) Creatinine or < 1.6 mg/dl ± Global Ischemia Systolic BP or < 160 mmhg Stenosis or < 80% -OR- Uncertain about need for revascularization (ASTRAL)
Are there exceptions? May 1 st, 2013, Restenosis (crushed stent) within a solitary functioning kidney Creatinine 361 µmol/l Blood urea nitrogen 47 mmol/l
6 5 BUN Creatinine Renal Intervention 138 115 4 92 3 69 2 46 1 23 0 12/21/05 12/21/06 12/21/07 12/21/08 12/21/09 12/21/10 12/21/11 12/21/12 12/21/13 0
RCT in Ischemic Nephropathy? Medical Therapy Stent + Med Rx Worse No Δ Better Worse No Δ Better
Conclusion 1. Renal artery revascularization is rarely indicated in people with atherosclerotic renal artery stenosis 2. Medical therapy, including cholesterol lowering and blood pressure control, is the standard of care for these individuals.