Renal Artery Stenosis : does it matter any more?
Philip A Kalra Consultant and Honorary Professor in Nephrology, Salford Royal Hospital and University of Manchester, UK Lead Nephrologist : ASTRAL trial UK lead : CORAL trial
Talk outline
Current outcomes for patients with ARVD Rationale for renal revascularization RCT of renal revascularization in atherosclerotic RAS Large single centre studies in high-risk patients Techniques for identifying responders to revascularization Atherosclerotic renovascular disease
FMD Epidemiology of incident ARVD in US citizens aged > 65 years Kidney Int 2005; 68(1):293-301
Prevalence 54 cases per 1000 = 0.54% Incidence 37 cases per 1000 per year
New-onset clinical events after ARVD diagnosis (% per year): ARVD Non-ARVD (n=5875) (n=1,085,250) AHD 30.6 7.4 CHF 19.6 5.7 RRT 2.9 0.1 Death 16.3 6.4 CVS co-morbidity and ARVD
45% 40% 35% 30% 25% 20% % with RAS 15% 10% 5% 0% CAD CCF PVD AAA CVA Harding Olin MacDowall Choudri Kuroda JASN 1990 Lancet 1998 BMJ 1990 AmJ Med 1990 Stroke 2000 Salford Renovascular database Outcomes of 563 ARVD patients (RAS > 50%) compared to
909 all-cause CKD patients (CRISIS study - patients with ARVD excluded)
eGFR 33 ml/min in both groups; DM in 29% (ARVD) vs 36% Other CKD
ARVD
Survival – non-dialysis CKD Other CKD
ARVD
Survival after haemodialysis start
D Vassallo et al, Kidney Blood Pressure Research, 2016
Cohort years End stage kidney Cardiovascular Mortality disease events (% per year) (% per year) (% per year)
1986-2000 4.0 6.4 15.9 (n=265)
2001-2004 4.7 8.2 15.4 (n=235)
2005-2008 2.9 6.5 10.7 (n=287)
2009-2014 2.9 6.0 13.8 (n=85)
Clinical presentations of ARVD that merit consideration of renal revascularization Cardiac Renal ‘Flash’ pulmonary Acute kidney injury oedema Prevention of severe Improve ‘congestion’ RAS → RAO (cardio-renal disease) ‘Rapid’ deterioration Pre-coronary or in renal function carotid surgery Patients who need Blood pressure RAA blockade but Control of severe intolerant hypertension
Case 1 : 76 yrs old male
Bilateral 90% RAS – 2 x attempts at revascularization 5 yrs earlier by cardiologists in London referred with deteriorating renal function BP 127/53 on verapamil, candersartan, indapamide Urine PCR 2 g/mol USS kidneys : right 9.5cm, left 10 cm
creatinine eGFR – 2 yrs earlier 147 46 – May 2011 203 31 – August 219 26 Renal revascularization August 2011
ml/min
50 45 40 35 30 25 eGFR 20 15 10 5 0 2009 Aug-11 Case 2
Male aged 53 Hypertension (175/90) Serum creatinine 180mol/l Kidney sizes : L 9.8cm; R 11.3cm Angiogram : L 80% RAS; R normal Randomised to revascularization in ASTRAL
Case 2 : Follow-up
Feb 2001 290 mol/l March 2001 369 mol/l April 2001 535 mol/l May 2001 997 mol/l June 2001 commenced dialysis
RCTs in ARVD
Level 1 evidence now derived from the following RCTs in ARVD :
- EMMA study (49 patients) – Plouin et al, 1998 - DRASTIC (106) – Van Jaarsfeld et al, 2000 - Scottish and Newcastle (55) – Webster et al, 1998
- STAR (160) – Beutler et al, 2009 - ASTRAL (806) – N Eng J Med, 2009 - CORAL (947) – N Eng J Med, 2013
Many single and multi-centre prospective and retrospective studies showing benefit of revascularization in a proportion of patients
New England Journal of Medicine 2009; 361 : 1953-62 LABORATORY and BP DATA BY RANDOMISED TREATMENT Revasc. Medical P-value SCr (μmol/l) 179 178 0.9 88 μmol/l = 1 mg/dl (66 – 551) (64 – 750) Rapid increase in SCr 12% 12% 0.9 GFR (ml/min) 40.3 39.8 0.7 (5.4 – 124.5) (7.1 – 121.7) Albumin:Creatinine ratio 70.2 71.7 0.9 (0 – 2740) (0 – 2466) Systolic BP (mm Hg) 149 152 0.07 (87 – 270) (90 – 241) Diastolic BP (mm Hg) 76 76 0.6 (45 – 120) (46 – 130) Cholesterol (mmol/l) 4.68 4.71 0.8 (0.1 – 14.8) (1.9 – 9.6) Average RAS = 76%; 20% non-compliance with revascularization
Change in renal function
Change in Systolic blood pressure Macrovascular events
Survival
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.,
on behalf of the CORAL Investigators
CORAL : Inclusion criteria and primary outcome measure
INCLUSION CRITERIA PRIMARY OUTCOME Clinical Syndrome: • Composite of major • Hypertension ≥2 anti-hypertensive cardiovascular or renal events: medications, OR – Cardiovascular or Renal • Renal dysfunction defined as Stage 3 Death or greater CKD – Stroke
-AND- – Myocardial Infarction – Heart Failure Hospitalization Atherosclerotic Renal Artery Stenosis: – Progressive Renal • Angiographic: ≥ 60% and < 100%, OR Insufficiency • Duplex: systolic velocity of >300 – Permanent Renal cm/sec, OR Replacement Therapy • Core lab approved MRA, OR • Core lab approved CTA
Screening and Enrollment Baseline Characteristics
Baseline Characteristics of the Study Population According to Treatment Group Characteristic Stent + Medical Medical • No significant N = 459 N = 472 differences in clinical Age (years) 69.3 ± 9.4 69.0 ± 9.0 and angiography Male gender (%) 51.0 48.9 characteristics White race (%) 91.5 90.9 Black race (%) 7.0 7.0 • Approximately 20% Body mass index (kg/m2) 28.2 ± 5.3 28.7 ± 5.7 global ischemia Systolic blood pressure (mmHg) 149 ± 23.2 150.4 ± 23.0 • Stenosis severity Estimate GFR (ml/minute) 58.0 ± 23.4 57.4 ± 21.7 similar to FDA Medical history and risk factors (%) approval trials 1-3 Diabetes 32.4 34.3 Prior myocardial infarction 26.5 30.2 1. Rocha-Singh K et. al. ASPIRE-2. JACC History of heart failure 12.0 15.1 2005;46:776-83 Smoking in past year 28.0 32.2 2. Rocha-Singh K et. al. RENAISSANCE. CCI 2008;72:853-62 Angiography 3. Jaff MR, et. al. HERCULES. CCI % stenosis (core lab) 67.3 ± 11.4 66.9 ± 11.9 2012;80:343-50 % stenosis (investigator) 72.5 ± 14.6 74.3 ± 13.1 Global ischemia (%) 20.0 16.2 Bilateral disease (%) 22.0 18.1
Results: Primary Endpoint Clinical Events Stent plus medical therapy
Medical therapy
Stent + Medical Therapy 35.1%, 3-years Medical Therapy 35.8%, 3-years HR 0.94 [0.76-1.17], p = 0.58
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 US Medicare : Trends in revascularization 1992-2010 RR 1.4 1.2
1 ASTRAL published 0.8 ↓ 0.6 0.4 0.2 0 1992 1994 1996 1998 2000 2002 2010
In 2004 approx 30,000 renal stent procedures performed annually in US Limitations of the large RCTs
ASTRAL – Power calculation based on limited data in a study with selection bias (Harden et al, Lancet, 1998) – 20% non-compliance with revascularization – large proportion had mild and ‘asymptomatic’ RAS; many probably clinically insignificant – Concern that trial entry criteria led to many patients being revascularized outside the trial
CORAL – Largely lower risk hypertensive population; eGFR 58 ml/min – Many higher-risk patients excluded (despite radiology core lab)
What have we learned from the RCTs?
Revascularization does not improve outcomes in majority of unselected patients with ARVD These conclusions only apply to the patient phenotype included in the studies Some patients do benefit from revascularization – who are they and can we reliably identify them?
Don’t forget the benefits of But at least no more ‘drive-by’ medical therapy shootings!
Our favourite cases
65 yr old lady with 3 episodes of acute pulmonary oedema in 12 months BP 220/88 on 3 agents Echo – moderate to severe systolic dysfunction (EF 35%) and LVH Claudication; right carotid stenosis but no history of IHD ↓GFR from 60 to 22 ml/min in 15 months MRA bilateral 80-90% RAS; right kidney 9 cm, left 11cm Changes in isoSK-GFR and
GFR cardiac MR parameters (ml/min) 35 Pre- 4 30 revasc months 25 EF (%) 42 53 20 15 Pre Post 10 LVEDV 200 106 5 (ml) 0 Left Right LV mass 201 133 GFR GFR (g) Am J Kid Dis 2014; 63(2) : 186-97
‘High-risk’ ARVD phenotypes (RAS > 50%): Ritchie J et al, Am J Kid Dis 2014; 63(2) : 186-197
Salford RVD database : Prospectively collected data on all diagnosed ARVD patients 1998 to current (n>900) Revascularization performed according to physician preference; on clinical grounds; or RCT randomisation
High-risk categorisation : – Acute pulmonary oedema : rapid onset cardiac decompensation; no alternative aetiology – ‘Resistant hypertension’ : >140/90 despite 3 or more agents – Deteriorating renal function : creatinine 1.2x or 100 umol/l > baseline within previous 6 months
Low-risk = none of the above
Recommendations for renal revascularization Haemodynamically significant RAS with:
– Recurrent unexplained congestive heart failure (Class I, evidence level B) – Resistant / malignant hypertension (Class IIa, evidence level B) – Progressive CKD and bilateral RAS (Class Iia, 2005 evidence level B).
Effect of revascularization in patients with ARVD and high-risk clinical features: a single-center observational study (DM Vassallo et al)
ARVD database 1986 – current (894 patients)
Patients with >70% unilateral or bilateral renal artery stenosis together with one or more high-risk presentations (n=131; 15%) : - flash pulmonary oedema – severe hypertension (SBP >160, DBP >100, on > 3 anti-BP meds) – rapidly deteriorating renal function (decline in eGFR worse than 3 ml/min/yr = worse 25% of whole population)
they were compared to ‘control’ patients with > 70% RAS who did not exhibit these features (n= 144; 16.5%) Hazard ratio for effect of renal revascularization upon end-points in control and high-risk patients
Control P value High-risk P n=144; 43 PTRAS n=131; 55 PTRAS value (30%) (43%) Death 1.20 (0.61-2.38) 0.60 0.64 (0.33-1.26) 0.20
ESKD 1.00 (0.60-1.66) 1.00 0.64 (0.37-0.96) 0.03
CVE 1.06 (0.65-1.72) 0.82 0.66 (0.42-1.04) 0.07
Any 1.12 (0.69-1.82) 0.65 0.70 (0.45-1.09) 0.12 outcome Flash pulmonary oedema : HR for death with PTRAS 0.38 (0.15-0.96; p=0.04)
Deteriorating renal function : HR for ESKD with PTRAS 0.44 (0.24-0.82; p=0.01) Techniques to detect responders to PTRAS
Pressure wire studies Pressure wire criteria Fractional flow reserve (FFR) Duplex ultrasound MR perfusion imaging – Volume : GFR BOLD imaging MR perfusion imaging - Parenchymal Volume (PV) : SK-GFR of stented kidneys
Number Mean SD Range PV : SK-GFR Deteriorated (>15% 5 4.86 1.1 3.7- 5.8 Deterioration renal function) Stable (-15 to 18 6.38 2.5 3.6- 12.7 15%) Improved (>15% 7 17.49 15.2 6- 45.4 Improvement renal function) BOLD imaging in ARVD : Textor S et al, Kidney Int 2012 High grade proteinuria = bad outcome in ARVD (> 0.6 g/day) 3 main considerations prior to possible revascularization
Does the patient have a key clinical phenotype (eg FPE, declining function, severe hypertension)?
Is the RAS physiologically or haemodynamically significant?
What is the state of the kidney beyond the RAS? – Renal atrophy (< 7 cm) – Significant proteinuria = severe parenchymal disease – Determine kidneys with greatest ischaemic stress yet viable tissue (‘Hibernating’ kidney tissue)
Revascularization in atherosclerotic RAS is NOT for all but it should be for some…….. Definite indications Possible indications
Very severe hypertension (eg SBP Severe or dialysis > 180 on 4+ drugs) : individual dependent AKI case basis Patients who require/would Rapidly deteriorating renal function benefit from Renin : individual case basis angiotensin blockade but If rapidly deteriorating renal function and severe hypertension who are intolerant occur together Recurrent acute heart Patients with ‘hibernating’ renal failure parenchyma Chronic heart failure ? Preventing renal atrophy long term?
Renal Artery Stenosis : does it matter any more? It sure does :
– Patients with atherosclerotic RVD have very high CVS risk – They should all receive comprehensive vascular protective medication – A minority of patients will benefit from renal revascularization : it is important to identify them