Benefits of Medical Therapy Plus Stenting for Renal Atherosclerotic Lesions

BACKGROUND:

Atherosclerotic renal artery stenosis is a common problem for which there is no clear
consensus on diagnosis or therapy. There likely exists a progression in which renal ischemia
leads to neuroendocrine activation, hypertension, and renal insufficiency resulting in
acceleration of atherosclerosis, further renal dysfunction, and development of left
ventricular hypertrophy. These events in turn lead to adverse clinical events.

Renal artery stenosis is one of the two major known causes of hypertension and occurs in
1-5% of hypertensive patients. In patients with accelerated hypertension, the prevalence of
renal artery stenosis is much higher, ranging from 10-40%. Renal artery stenosis, when
occurring bilaterally, or in a solitary kidney, is a significant cause for end-stage renal
disease, accounting for several percent of patients with end-stage renal disease.
Clinically, atherosclerotic renal artery stenosis is a major problem primarily in older
patients, and is often seen in long-standing hypertensives whose blood pressure becomes very
difficult to control. Of major significance is the progressive nature of atherosclerotic
renal artery stenosis, progressing at the rate of about 10% per year (45-60% progression
rate in 4-7 year follow-ups). Over this time period, 10-15% of patients develop total renal
artery occlusion. If the renal artery stenosis is greater than 75% when detected, 40% of
patients develop total occlusion. Due to the progressive nature of atherosclerotic lesions,
the decline in renal function in some individuals, and difficult-to-control hypertension,
the medical community has sought to detect those patients in whom intervention would be
beneficial. This has been extremely difficult to achieve and tests to date have not been
uniformly predictive, including peripheral vein plasma renin activity, renal vein renin
activity, captopril-stimulated nuclear medicine renal scans, etc.

Since approximately 50% of patients with unilateral renal artery stenosis of significant
degree (definitions vary) benefit from surgical intervention, enthusiasm has continued with
the advent of renal artery angioplasty. The entire field is moving very quickly. However,
there are neither current data nor prospective studies indicating the benefit of renal
artery angioplasty plus stents. Studies over the last decade have shown that balloon
angioplasty alone is associated with a high rate of recurrence in patients with
atherosclerotic renal artery stenosis. In the present climate, there is great enthusiasm to
perform angioplasty plus stent placement in atherosclerotic renal artery stenosis, without
supporting data for efficacy compared to medical management alone. Angioplasty and stent
placement in the renal arteries had been the domain of interventional radiologists, but
recently, interventional cardiologists are also performing these procedures. The questions
as to who will benefit from intervention and which intervention to use have not been
answered. Renal artery angioplasty and stent placement subjects the patient to procedural
risks, as well as increased cost, when compared to aggressive antihypertensive medication
and risk factor medication and therapy.

DESIGN NARRATIVE:

This randomized, multicenter clinical trial will contrast the effect of optimal medical
therapy alone to stenting with optimal medical therapy, on a composite of cardiovascular and
renal endpoints: cardiovascular or renal death, myocardial infarction, hospitalization for
congestive heart failure, stroke, doubling of serum creatinine level, and need for renal
replacement therapy. These endpoints will be evaluated by a clinical events committee masked
to treatment assignment. The secondary endpoints will 1) evaluate the mechanisms linked to
clinical events; 2) describe differential effectiveness in critical end-organs; 3) determine
the value of stenting from the patient and the health policy perspectives, measured as
quality of life and cost-effectiveness; and 4) evaluate for clinically relevant differences
in treatment effectiveness within the primary endpoint.

Patients will undergo a baseline evaluation to determine eligibility. Approximately 1,080
patients will be randomized to optimal medical therapy alone or to stenting with optimal
medical therapy at an estimated 100 clinical sites. Initially, patients will be followed at
2-week intervals, until blood pressure is at target or up to 2 months. Follow-up visits will
be mandated at 2 weeks, every 3 months for the first year and annually thereafter.
Coordinator visits will also occur semi-annually.

The CORAL Study Chair is Lance Dworkin, MD, Brown University, Providence, RI. The CORAL
Study Co-Chair is William Henrich, MD, University of Texas, San Antonio, TX. The Principal
Investigators of the CORAL Clinical Coordinating Center are Christopher Cooper, MD,
University of Toledo Health Science Campus, Toledo OH, and Timothy Murphy, MD, Brown
University, Providence, RI.

The Principal Investigator of the Angiographic Core Laboratory is Alan Matsumoto, MD,
University of Virginia, Charlottesville, VA. The Principal Investigator of the GFR and
Biochemistry Core Laboratory is Michael Steffes, MD, University of Minnesota, Minneapolis,
MN. The Principal Investigator of the Economics and Quality of Life Core Laboratory is David
Cohen, MD, Mid-America Heart Institute, St. Luke's Hospital, Kansas City, MO. The Principal
Investigator of the Data Coordinating Center is Donald Cutlip, MD, Beth Israel Deaconess
Medical Center, Boston, MA. For additional information about the CORAL trial, please refer
to the CORAL website (link given below).

INCLUSION CRITERIA:

1. Either

1. Documented history of hypertension on two or more anti-hypertensive medications
OR

2. Renal dysfunction, defined as Stage 3 or greater chronic kidney disease (CKD)
based on the new National Kidney Foundation (NKF) classifications (estimated
glomerular filtration rate [GFR] less than 60 mL per minute per 1.73 m^2,
calculated by the modified Modification of Diet in Renal Disease [MDRD] formula)

2. One or more severe renal artery stenoses by any of the following pathways:

a. Angiographic: greater than or equal to 60% and less than 100% by renal angiogram
OR b. Duplex: systolic velocity of greater than 300 cm/sec OR c. Core Lab approved
Magnetic Resonance Angiogram (MRA) (refer to the protocol for specific criteria)
demonstrating stenosis greater than 80% OR stenosis greater than 70% with spin
dephasing on 3D phase contrast MRA OR stenosis greater than 70% and two of the
following: i. Ischemic kidney is greater than 1 cm. smaller than contralateral kidney
ii. Ischemic kidney enhances less on arterial phase iii. Ischemic kidney has delayed
Gd excretion iv. Ischemic kidney hyper-concentrates the urine v. 2-D phase contrast
flow waveform shows delayed systolic peak vi. Post-stenotic dilatation d. Clinical
index of suspicion combined with a Core Lab approved Computed Tomography Angiography
(CTA) demonstrating Stenosis is greater than 80% by visual assessment on high quality
CTA Stenosis is greater than 70% on CTA by visual assessment and there are two of the
following i. The length of the ischemic kidney is greater than 1 cm. smaller than
contralateral kidney ii. Reduced cortical thickness of ischemic kidney iii. Less
cortical enhancement of ischemic kidney on arterial phase iv. Post-stenotic
dilatation

EXCLUSION CRITERIA:

1. Unable to provide informed consent

2. Unable or willing to comply with study protocol or procedures

3. Must be greater than 18 years of age

4. Fibromuscular dysplasia or other non-atherosclerotic renal artery stenosis known to
be present prior to randomization

5. Pregnancy or unknown pregnancy status in female of childbearing potential

6. Participation in any drug or device trial during the study period, unless approved by
the Steering Committee

7. Prior enrollment in the CORAL study

8. History of stroke within 6 months, if associated with a residual neurologic deficit*

9. Any major surgery, major trauma, revascularization procedure, unstable angina, or
myocardial infarction 30 days prior to study entry*

10. Any planned major surgery or revascularization procedure, outside of the randomly
allocated renal stenting indicated by the protocol, after randomization*

11. Hospitalization for heart failure within 30 days*

12. Comorbid condition causing life expectancy of less than or equal to 3 years*

13. Allergic reaction to intravascular contrast, not amenable to pre-treatment

14. Allergy to stainless steel

15. Allergy to all of the following: aspirin, clopidogrel, ticlopidine

16. Known untreated aneurysm of the abdominal aorta greater than 5.0 cm.*

17. Previous kidney transplant

18. a. Stenosis of greater than 50% of a previously treated revascularized renal artery
OR b. Treatment of any renal artery stenosis within the past 9 months (roll-in
patients can have prior treatment on the contralateral side)

19. Kidney size less than 7 cm. supplied by target vessel

20. Hydronephrosis, nephritis or other known cause of renal insufficiency, not due to
large vessel renal artery stenosis

21. Visualized stenosis of only an accessory renal artery supplying greater than 1/2 of
the ipsilateral renal parenchyma, without stenosis in a dominant renal artery

22. Local lab serum Cr greater than 4.0 mg/dl on the day of randomization*

23. Presence of a renal artery stenosis not amenable for treatment with a stent, known to
be present prior to randomization

1. The index lesion cannot be treated with a single stent (i.e. greater than 18 mm.
in length)

2. The placement of a stent will necessitate covering a renal artery branch renal
artery with a stent

3. The stenosis is in an artery less than 3.5 mm. in diameter

4. The stenosis involves a segmental renal artery branch

24. Abrupt vessel closure or dissection after diagnostic angiography [NOTE: Patients with
abrupt vessel closure or dissection as a result of diagnostic angiography will not be
randomized but will undergo stent revascularization, receive optimal medical therapy
and will be followed for the full study period] *Roll-in patients do not need to meet
these inclusion/exclusion criteria