SVS Clinical Research Priorities Mesenteric/Renal

SVS Clinical Research PrioritiesMesenteric/Renal

Kimberley J. Hansen, MD

Wake Forest Baptist Health

Renal artery clip

hypertension

Surgery for renal reconstruction

Function tests: Blood flow, sodium excretion

Nephrectomy for

hypertension with a small

kidney

Cooperative study of renovascular hypertension

Urgent bilateral nephrectomy for treatment resistant, malignant HTN

Statin therapy

ARB RxAdvanced imaging:

MRA, CTA

Early imaging: intravenous pyelography

scan Stents

Prospective trials:Med Rx vs Stent

TherapyCORALASTRAL

STARRAVE

Small, randomized trials

Med Rx vs PTRA

ACE inhibitor Rx

Calcium Blockers

PTRA introduced

Improved surgery

1930 1940 1950 1980 1990 20001960 1970


Prevalence of Renovascular Lesions

• CHS Participants > 65 years 6-7%• Patients – Coronary Arteriography 6-18%• Patients – Aortography 16-40%• ‘NEW’ Hypertensives > 60 years 20-

30%

DBP > 110/mmHg

J Vasc Surg 2002;36:443-451, Am Heart J 1998,136:913-918, Cathet Cardiovasc Diagn 1994;32:8-10, J Am Soc Nephrol 1992;2:1608-1616, Am J Med 1990;88:46N-51N, Ann Vasc Surg 1998;12:17-22, J Vasc Surg 1993;18:433-440, Am J Med 2000;109:642-647, J Am Hypertension 1996;10:83-85,

Am J Med 1994;96:10-14, Int Angiol 1992;11:195-199


CMS PTRA-S

Procedures 1996 1998 2000Renal AngioplastyRenal StentBoth Renal Angioplasty and Stent

18961

133

192120258

219287420

Total, 5% fileExtrapolated to 100%

3837,660

57011,400

92618,520

Note. - Procedure totals are from 5% files for analysis of codes 35471, 37205, and both, respectively. Results from the 5% Part B files were multiplied by 20 to yield “extrapolated to 100%” totals.

AJR 2004; 183:561-568


PTRA-S per 100,000CMS Region 1996 1998 2000 % Increasea

KeystoneSoutheastSouthGreat LakesPacificSouthwestGreat WesternOtherMid-AtlanticNorth EastNational

122230251432385

381825

2641464030533914451938

578687623171709

622661

482387287253228223186178166142239

Note. - Overall utilization pooled for all regions is listed in the last row (these numbers differ slightly from the average of each region because of slight differences in number of beneficiaries among regions, particularly the low-utilization, sparsely populated “other” region). Average utilization in 2000 ranged from 26 to 87 per 100,000 (excluding “other”). CMS regions are Mid-Atlantic: DE, DC, IN, MD, OH, VA, WV; Southwest: AR, CO, LA, NM, OK, TX; Northeast: CT, ME, MA, NH, NY, RI, VT; Great Lakes: IL, IA, MI, MN, WI; Great Western: AK, ID, KS, MO, MT, NE, ND, OR, SD, UT, WA, WY; Keystone: NJ, PA; Southeast: AL, KY, MS, NC, SC, TN; South: FL, GA Pacific: AZ, CA, HI, NV; Other: Puerto Rico, Virgin Island. CMS = Centers for Medicare and Medicaid Services.aGrowth in annual procedure volume when compairing 2000 with 1996

AJR 2004; 183:561-568


Annual PTRA-S Volume

Physician Specialty 1996 (%) 1998 (%) 2000 (%) % of Increasea

CardiologyRadiologySurgeryOther

2,380 (31)4,700 (61)

300 (4)280 (4)

5,060 (44)5,380 (61)

480 (4)480 (4)

9,220 (50)7,660 (41)

760 (4)880 (5)

28763

153214

Total 7,660 11,400 18,520 142

Note. - Physicians identifying their specialty as cardiology or internal medicine are considered cardiologists in this table, those reporting their specialty as interventional radiology or radiology are identified as radiologists, and those reporting their specialty as vascular surgery or general surgery are categorized as surgeons. These specialties accounted for more than 95% of providers submitting claims for renal artery interventional procedures for each year.

aGrowth in annual procedure volume when comparing 2000 with 1996

AJR 2004; 183:561-568


Frequency of PTRA-S 2005National Inpatient Sample

Region Overall Weighted Frequency (SD)

% Hospitalization

Empirical RA-PTAS

Prophylactic RA-PTAS

SouthNortheastMidwest West

30,457 (2,484)15,300 (1,847)17,955 (1,634)12,221 (1,393)

0.200.200.200.16

23,63511,05513,5489,049

6,8224,2454,4073,172

Totals 75,933 - - 57,287 18,646

Source: National Inpatient Sample (Unpublished)

Estimated Health Cost Expenditure – 75,933 x (5,136 + 723) 444,891,447


Overall Averagea) Surgical renal artery reconstruction (RAR)?b) PTRA without stent placement?c) PTRAS with bare metal stents?d) PTRAS with drug-eluting stents?

2.922.922.851.00

1. For the treatment of patients with atherosclerotic RAS, how confident are you that the evidence is adequate to draw conclusions about safety and clinical effectiveness of the following renal artery interventions:

2007 MedCAC Voting QuestionsHighly Confident (5) – Not Confident (1)


Overall Averagea) Medicare patients with typical

comorbidities?b) Providers (facilities/physicians) in

community practice?

3.69

2.15

2. Based on the evidence presented, how confident are you that the published results apply to :



Overall Averagea) Surgical renal artery reconstruction (RAR)?b) PTRA without stent placement?c) PTRAS with bare metal stents?d) PTRAS with drug-eluting stents?

2.312.083.15N/A

3. Based on the evidence presented for patients with atherosclerotic RAS, how confident are you that compared to aggressive medical treatment alone there are improved key health outcomes attributable to the following co-interventions:



2007 MedCAC Voting Questions Strongly Agree(1) – Strong Disagree(5)

Overall Average2.23

4. Based on the evidence presented, should Medicare national coverage of any non-medical treatments for atherosclerotic RAS be limited only to patients enrolled in qualified clinical research studies?


Prospective Randomized Clinical Trials

• Single center, Malmö• Inclusion

< 70 yearsNo diabetesHypertension with unilateral RA stenosis

• RVH defined by RVRA’s• GFR estimated by Cr-EDTA clearance• Angiographic follow-up for all• PTRA primary/secondary patency 75%/90%

Surgical 96%/97%• PTRA HTN cured/improved 83%

Surgical 89%• Non-representative patient cohort

Significant difference baseline GFRPTRA crossover to surgery

• No Endoluminal stentsJ Vasc Surg 1993;18:841-850

PTRA versus Open Repair


Early Prospective Randomized TrialsTrial Patients

(n)Unilateral or

Bilateral Disease

Randomized Treatment

Duration of Follow-Up

Main Endpoints

Webster et alSNRASCO

55 Unilateral and bilateral, but two groups analyzed separately

Angioplasty v medical management

Patients reviewed at end of 4-week run-in period (baseline) then at 1, 3, and 6 months, then at 6-month intervals

Primary: BP and SCr at 6 months and the change in these from baseline

Plouin et alEMMA

49 Unilateral only Angioplasty (with or without stent insertion) v medical management

Patients reviewed at end of 2-6 week run-in period (baseline) then at 6 months

Primary: BP at termination* and the change from baselineSecondary: treatment score and incidence of complications

van Jaarsveld et alDRASTIC

106 Unilateral and Bilateral

Angioplasty v medical management

Patients reviewed every 1-3 months, and always at 3 and 12 months

Primary: BP at 3 and 12 months Secondary: treatment score, SCr, SCr clearance, patency, and incidence of complications

From Ives NJ, Wheatley K, Stowe RL, et al: Continuing uncertainty about the value of percutaneous revascularization in atherosclerotic renovascular disease: a meta-analysis of randomized trials. Nephrol Dial Transplant 2003;18:298-304 adapted with permission. *Termination defined as 6 months after randomization or earlier in cases of refractory hypertension (diastolic blood pressure > 1 to 4 mm/Hg despite maximal tolerated antihypertensive regimen. In such cases, blood pressure, treatment score, and SCr were determined prior to renal arteriograph.

Nephrol Dial Transplant 2003;18:298-304



• STent placement and blood pressure and lipid-lowering for prevention of progression of renal dysfunction caused by Atherosclerotic ostial stenosis of the Renal artery (Netherlands)

• Stenting versus angioplasty alone for ostial RAS• Primary ‘Technical’ Success

Stent 88%PTRA 57%

• Restenosis RateStent 14%PTRA 48%

• Primary endpoint: <20% Decline EFGRNo difference

• Secondary endpoints: HTN, heart and vascular events, mortalityNo difference

• ESRD or mortality in 10% patientsJ Nephrol 2003;16:807-812

STAR Study

Management Of Renovascular DiseaseOngoing Randomized Controlled Trails

•Angiopolasty and STent for Renal Artery Lesions (ASTRAL – United Kingdom)

•Renal Atherosclerotic ReVascularization Evaluation (RAVE – Canada)

•Nephrology Ischemic ThERapy (NITER – Italy)

•Renal Artery Stenting in HemoDynamic Atherosclerotic Renal Artery Stenosis (RADAR) – Europe and South America

•Cardiovascular Outcomes in Renal Atherosclerotic Lesions (CORAL – United States, Canada, Australia, and New Zealand



• Angioplasty and STenting For Renal Artery Lesions• Multicenter: 53 UK, 4 Australia• PTRA-S versus Best Medical Management

(Statins, Antiplatelet, Antihypertension THX)• 806 Patients (403 in each group); ‘Uncertain Worth’• Mean follow up: 33.6 months (all 12 months)

Mean degree RAS: 76% diameter reduction 60% > 70% stenosis

• Primary endpoint: rate of change EGFR• Secondary endpoints: HTN, heart and vascular events, mortality• No difference in 1o or 2o endpoints

N Engl J Med 2009;361:1953-1962

ASTRAL Trial



• Cardiovascular Outcomes in Renal Atherosclerotic Lesions• Multicenter: Enrolled 1050 patients (U.S., Canada, Australia, New

Zealand)• PTRA-S versus Best Medical Management• Primary endpoint: composite CV mortality, MI, CHF, CVA, Doubling SCr,

ESRD• Secondary endpoints: all cause mortality, EGFR, restenosis,

microvascular function, BP control• Renal artery stenoses measured PRIOR to randomization at angiography• Translesional pressure gradients before and after randomization• Distal embolic protection encouraged (complete balloon occlusion)• Recruitment/randomization closed 2010• Publication/presentation 1/2014 (C. Cooper)

Am Heart J 2006;152:59-66

CORAL Trial


Atherosclerotic Renovascular DiseaseMultivariate Analysis – Death or Dialysis

J Vasc Surg 2002;35:236-245

Variable ß Coefficient Hazard Ratio 95% C.I. P Value

Pre-Op EGFR -0.8555 0.43 0.34, 0.54 <0.001

Diabetes Mellitus 0.5313 2.14 1.15, 3.97 0.007

Prior CVA 0.4068 1.50 1.02, 2.22 0.042

Al-Occl 0.5078 1.66 1.19, 2.31 0.003

Pre-Op BP -0.2329 0.79 0.67, 0.94 0.006

BP Cure -0.6637 0.52 0.30, 0.88 0.014

EGFR No Change 0.9259 1.49 1.04, 2.13 0.028

EGFR Worse 0.1070 1.95 1.06, 3.61 0.032

(# Pts) Improved Unchanged Worsened Cured Improved Failed (%)Rees CR (1991) 14 36% 36% 29% 11% 5% 36% 39%Kuhn FP (1991) n/r n/r n/r n/r 22% 34% 44% 17%Joffre F (1992) 4 50% 50% 0% 27% 64% 9% 18%Hennequin LM (1994) 6 20% 40% 40% 7% 93% 0% 27%MacLeod M (1995) 16 25% 0% 40% 60% 17%van de Ven PJG (1995) n/r 33% 58% 8% 0% 73% 27% 13%

Dorros G (1995) 29 28% 28% 45% 6% 46% 48% 25%Henry M (1996) 10 20% 18% 57% 24% 9%Iannone LA (1996) 29 36% 46% 18% 4% 35% 61% 14%Harden PN (1997) 32 35% 35% 29% n/r n/r n/r 13%Blum U (1997) 20 0% 100% 0% 16% 62% 22% 17%Boisclair C (1997) 17 41% 35% 24% 6% 61% 33% 0%Rundback JH (1998) 45 18% 53% 30% n/r n/r n/r 26%Fiala LA (1998) 9 0% 100% 0% 47% 65%Dorros G (1998) 63 1% 42% 57% n/rTuttle KR (1998) 74 16% 75% 9% 2% 46% 52% 14%Gross CM (1998) 12 55% 27% 18% 0% 69% 31% 13%Henry M (1999) 48 29% 67% 2% 19% 61% 20% 11%

Rodriguez-Lopez JA (1999) 32 13% 55% 32% 26%van de Ven PJ (1999) 29 17% 55% 28% 15% 43% 42% 14%Baumgartner I (2000) n/r 33% 42% 25% 57% 28%Giroux (2000) 21 24% 47% n/rLederman (2001) 111 8% 78% 14% 30% 21%Bush (2001) 50 23% 51% 26% n/r n/r n/r n/rZeller (2004) 239 34% 39% 27% 54% n/r

Totals= 1017 22% 56% 22% 10% 51% 39% 19%n/r: Not ReportedSCr: Serum Creatinine

Renal Dysfunction

53%

Reference/Date Function response (%) HTN Response (%) Restenosis

46%

70%

75%

80%

53%

No change in mean SCr

No change in mean SCr

43%76%

Management of Renovascular DiseasePTRA-S and Ischemic Nephropathy


Chronic Mesenteric IschemiaPTVA+S vs. Open Repair

J Vasc Surg 2007;45:1162-11711

J Endovasc Ther 2010;17:540-5492

Ann Vasc Surg 2009;23:700-7123

Author (Source)

Method Symptomatic Relief

Morbidity Mortality10

Patency (1 yr)

Symptomatic Recurrence

(1 yr)

Atkins1 (Single Center)

Open Repair 90% 35% 2% 91% 7%

PTVA + S 87% 29% 3% 67% 25%

Gupta2 (Review)

Open Repair 94.4% 34.7% 4.5% 90.8% 22.4%

PTVA + S 87.8% 14.1% 4.1% 74.2% 21.7%

Oderich3 (Review)

Open Repair 94% 47% 7% 89% 7%

PTVA + S 89% 15% 3% 74% 25%


Acute Mesenteric IschemiaPercutaneous vs. Open Repair

J Vasc Surg 2011;53:698-705

Thrombotic - Embolic Occlusion

In-HospitalMortality

Thrombotic - Embolic Mortality

Open Repair 36% - 64% 50% 83% - 33%

Percutaneous Intervention

72% - 28% 39% 33% - 53%


Atherosclerotic Renovascular DiseaseSummary

• Severe Hypertension Key Clinical Characteristic Favoring Presence of Renovascular Disease

• Improved Renal Function Key Postoperative Result Favoring of Dialysis-free Survival

• Associations With Improved Renal Function• Severe Associated Hypertension• Bilateral Renovascular Disease With Bilateral

Reconstruction • Rapidly Deteriorating Renal Function

• Test(s) Physiologic Significance/Response

SVS Clinical Research Priorities Mesenteric/Renal

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