CORAL

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Cooper CJ, et al. "Stenting and Medical Therapy for Atherosclerotic Renal-Artery Stenosis". The New England Journal of Medicine. 2014. 370(1):13-22.
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Clinical Question

Among patients with hypertension or chronic kidney disease secondary to atherosclerotic renal artery stenosis, does renal artery stenting improve renal and/or cardiac outcomes?

Bottom Line

Renal artery stenting does not improve renal and cardiac clinical outcomes in patients with hypertension or chronic kidney disease secondary to atherosclerotic renal artery stenosis.

Major Points

Symptomatic renal artery stenosis can present with hypertension (acute, severe, or resistant), chronic kidney disease secondary to ischemic nephropathy, recurrent flash pulmonary edema and refractory heart failure. While control of blood pressure in renovascular disease with anti-hypertensive medications is the mainstay of therapy, percutaneous transluminal renal angioplasty (PTRA) with stenting is becoming an increasingly common procedure performed in patients refractory to medical management alone.

The benefit of stenting in symptomatic renal artery stenosis was investigated in ASTRAL published in 2009. The primary endpoint in ASTRAL was the change in renal function, and no difference was found between stented and non-stented groups. This study was criticized for using a surrogate outcome as the study endpoint, excluding patients most likely to benefit from treatment (high degree of stenosis), and inclusion of patients with potentially insignificant stenoses (50-70%). The percent stenosis and trans-lesional pressure gradient cutoffs at which a lesion is considered significant is debatable and not well-defined in the literature[1]. Furthermore, angiography has been found to grossly over-estimate the severity of RAS, further complicating diagnosis of significant disease[1].

The 2014 CORAL (Cardiovascular Outcomes in Renal Atherosclerotic Lesions) randomized 967 patients with either hypertension or chronic kidney disease secondary to renal artery stenosis to optimal medical therapy with or without percutaneous renal stenting. Patients were followed for a median of 3.6 years. Compared to ASTRAL, CORAL was designed to have a primary clinical outcome as opposed to a surrogate outcome, and excluded patient populations felt to have insignificant stenoses. This was achieved by only including patients with stenoses of 80-99% and those with 60-79% if their trans-lesional systolic pressure gradient was >20 mmHg.

The study found no difference in the combined outcome of renal and cardiovascular events (stroke, myocardial infarction, congestive heart failure hospitalization, progressive renal insufficiency, or need for permanent renal replacement therapy). All individual endpoints in the combined outcome were also non-significant. Systolic pressure did not significantly differ between both groups (only -2 mmHg in the stented population), but fell the same in both groups (15.6mmHg vs. 16.6mmHg)[2].

Multiple criticisms of this trial exist. The similar drop in systolic pressure suggested that both groups were not on fully optimized anti-hypertensive therapy (average # of hypertensives: 3.5 vs 3.3)[2]. In addition, 210 out of 5322 potential participants screened were withdrawn by the physician - presumably many of these patients were felt by their physicians to benefit from stenting due to their severity of disease. Finally, as there are no agreed definitions defining a significant lesion, many patients with less severe stenosis (average stenosis in stented group: 67%) may not have benefited due to their mild disease. However, a subanalysis by the authors of participants with >80% stenosis also showed no benefit.

A Cochrane systematic review published in 2015 (including ASTRAL & CORAL) concluded balloon angioplasty (with or without stenting) conferred no benefit in cardiovascular or renal outcomes. Intervention did provide a small reduction (0.2) in the number of anti-hypertensives required with a small reduction in diastolic BP (-2 mmHg).[3]

Guidelines

ACC/AHA Management of peripheral arterial disease (2005 and 2011, adapted)[4]
Note: These guidelines do not reflect the outcomes of this trial.

  • Percutaneous revasularization:
    • Is reasonable if hemodynamically significant RAS and accelerated hypertension, resistant hypertension, malignant hypertension, hypertension with an unexplained unilateral small kidney, and hypertension with intolerance to medication (Class IIA, Level of Evidence: B)
    • Is reasonable if RAS and progressive chronic kidney disease with bilateral RAS or a RAS to a solitary functioning kidney (Class IIA, Level of Evidence: B)
    • May be considered if RAS and chronic renal insufficiency with unilateral RAS (ClassIIb, Level of Evidence: C)
    • Is indicated if hemodynamically significant RAS and recurrent, unexplained HF or sudden, unexplained pulmonary edema (Class I, Level of Evidence: B)
  • Is reasonable if hemodynamically significant RAS and unstable angina (Class IIA, Level of Evidence: B)

Design

  • Multicenter, randomized, open-label, randomized control trial
  • N=947
    • Renal artery stenting with optimal medical therapy (n=495)
    • Optimal medical therapy (n=472)
  • Follow-up: Median 3.6 years
  • Analysis: Intention-to-treat
  • Primary outcome:
    • Time to a major renal or cardiovascular event (Stroke, myocardial infarction, congestive heart failure hospitalization, progressive renal insufficiency, need for permanent renal replacement therapy)
  • Secondary outcomes:
    • Individual components of primary endpoint
    • Death from cardiovascular causes
    • Death from renal causes
    • Death from all-cause mortality

Population

Inclusion Criteria

  • Severe renal artery stenosis, angiographically defined as >80% but <100%, OR, >60% but <80% with systolic pressure gradient of >20 mmHg
    • All angiograms were analyzed with a valaidated vascular analysis program
    • The use of duplex ultrasonography, magnetic resonance angiography, and computed tomographic angiography became allowable as an alternative to angiography partway through the enrollment period

And either,

  • Hypertension with sBP >=155mmHg while on two or more antihypertensive medications
    • The threshold of 155mmHg was removed partway through the enrollment period

Or,

  • Chronic Kidney Disease, defined as GFR<60ml/min/1.73m^2 by the MDRD formula
    • this criteria was added partway through the enrollment period

Exclusion Criteria

  • Fibromuscular dysplasia
  • Chronic kidney disease from causes other than ischemic nephropathy
  • Serum creatinine >354 mcmol/L (4.0mg/dL)
  • Kidney < 7cm
  • Lesions could not be treated with a single stent

Baseline Characteristics

From the stenting plus medical therapygroup.

  • Demographics: Age 69.3y, 51% male, 7% Black
  • Weight: BMI: 28.2
  • Blood Pressure: sBP: 149.9 mmHg, 29.2% of patients at target level
  • Renal function: eGFR: 58 ml/min/1.73cm^2, 49.6% Stage >=3 CKD
  • Method of Stenosis Identification:
    • Angiography: 68.4%
    • Duplex ultrasonography: 25.5%
    • CT Angiography: 4.4%
    • MR Angiography: 1.7%
  • Co-morbidities:
    • Diabetes: 32.4%
    • Prior MI: 26.5%
    • History of heart failure: 12.0%
    • Smoking in past year: 28%
    • Hyperlipidemia: 89.4%
  • Angiographic findings:
    •  % Stenosis by core lab: 67.3%
    •  % Stenosis by investigator: 72.5%
    • Global ischemia: 20.0%
      • >60% stenosis of all arteries supplying both kidneys (or of single functioning kidney)
    • Bilateral disease: 22%
      • Defined as stenosis of >60% of at least one artery supplying each kidney

Interventions

  • Randomization in 1:1 ratio in blocks of four
  • Optimal medical therapy consist of:
    • Anti-platelet therapy as per guidelines
    • Anti-hypertensives, targeting 140/90 (130/80 if DM or CKD): Candesartan +- hydrochlorothiazide (Atacand), amlodipine-atorvastatin (Caduet)
    • Dyslipidemia, titrated to guideline targets: Atorvastatin-amlodipine (Caduet)
    • All medications were provided free of charge
  • Stenting consisted of:
    • Placement of Palmaz Genesis stent (Cordis)
    • Predilation at the discretion of the investigator
    • Stenting of all arteries >60%
    • Either single or multiple procedures if patient had multiple stenoses

Outcomes

Presented as stenting vs. OMT. Statistics only given when provided by authors.

Primary Outcome

Time to Major Cardiovascular or Renal Event

Defined as stroke, myocardial infarction, congestive heart failure hospitalization, progressive renal insufficiency, or need for permanent renal replacement therapy.

35.1% vs. 35.8%; HR 0.94, P=0.58

Secondary Outcomes

All secondary outcomes were not statistically significant.

Subgroup Analyses

Pre-specified subgroup analyses defined by sex, race, presence of global ischemia, and presence of diabetes in respect to the primary endpoint were all statistically insignificant.

Additional Data

Systolic Blood Pressure

-2.3mmHg (95% CI -4.4 to -0.2), P = 0.03

Stenosis Pre and Post Stenting

68% (+-11%) reduced to 16% (+-8%)

Serious Adverse Events

Arterial dissection in stent group: n = 11

Criticisms

  • Patients not optimized on anti-hypertensive therapy (similar reduction in blood pressure of 15-16 mmHg in both groups)
  • Withdrawal of patients by treating physician whom likely have greater severity of disease
  • Inclusion of patients with mild stenosis which may not benefit from percutaneous intervention
  • Only moderate correlation between angiographic stenoses and hemodyanmically significant stenoses

Funding

  • National Heart, Lung, and Blood Institute (NHLBI)
  • AstraZeneca (Medication donation)
  • Pfizer (Medication donation, financial support)
  • Cordis (Angioguard device, financial support)

Further Reading

  1. 1.0 1.1 Mangiacapra F et al. Translesional Pressure Gradients to Predict Blood Pressure Response After Renal Artery Stenosis in Patients with Renovascular Hypertension. Circ Cardiovasc Interv. 2010;3:00-00.
  2. 2.0 2.1 White JC. 2014. The “Chicken Little” of Renal Stent Trials: The CORAL Trial in Perspective. J Am Coll Cardiol Intv. 2014;7(1):111-113.
  3. Jenks S, et al. "Balloon angioplasty, with and without stenting, versus medical therapy for hypertensive patients with renal artery stenosis." Cochrane Database of Systematic Reviews 2014, Issue 12. Art. No.: CD002944.
  4. Anderson JL, et al. "Management of patients with peripheral artery disease (compilation of 2005 and 2011 ACCF/AHA guideline recommendations): a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines." Circulation. 2013;127(13):1425-1443.