CORAL

Published

Cooper CJ, et al. "Stenting and Medical Therapy for Atherosclerotic Renal-Artery Stenosis". The New England Journal of Medicine. 2014. 370(1):13-22.
PubMed • Full text • PDF • ClinicalTrials.gov

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 or cardiac clinical outcomes in patients with hypertension or chronic kidney disease due to atherosclerotic renal artery stenosis.

Major Points

Symptomatic renal artery stenosis (RAS) can lead to severe or resistant hypertension, ischemic nephropathy, recurrent flash pulmonary edema, and refractory heart failure. While control of blood pressure in renovascular disease with antihypertensive medications is the mainstay of therapy, percutaneous transluminal renal angioplasty (PTRA) with stenting has become 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 (2009). The primary endpoint in ASTRAL was the change in renal function, and no difference was found between patients in the stented and non-stented groups. ASTRAL was criticized for using a surrogate endpoint as the study's primary outcome, excluding patients with severe stenosis who may be most likely to benefit from treatment, and including patients with potentially insignificant stenoses in the 50-70% range. Stenosis severity and trans-lesional pressure gradient cutoffs at which a lesion is considered significant is not well defined. Furthermore, angiography has been found to grossly overestimate the severity of RAS, further complicating diagnosis of significant disease.

The 2014 Cardiovascular Outcomes in Renal Atherosclerotic Lesions (CORAL) study randomized 967 patients with RAS complicated by hypertension or CKD to optimal medical therapy with or without percutaneous renal stenting. Patients were followed for a median of 3.6 years. In contrast to the prior ASTRAL study, CORAL's primary endpoint was a clinical outcome, and CORAL excluded patients with 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 mm Hg.

CORAL 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 mm Hg in the stented population), but fell the same in both groups (15.6 vs. 16.6 mm Hg).

The trial had multiple limitations. The similar drop in systolic pressure suggested that both groups were not on fully optimized antihypertensive therapy (average number of hypertensives: 3.5 vs. 3.3). In addition, 210 out of 5,322 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 upon 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% stenoses also showed no benefit.

A Cochrane systematic review published in 2015 included ASTRAL and CORAL, and concluded that balloon angioplasty (with or without stenting) conferred no benefit in cardiovascular or renal outcomes. The intervention did provide a small reduction (0.2) in the number of antihypertensives required with a small reduction in diastolic BP (-2 mm Hg).

Guidelines

ACC/AHA Management of peripheral arterial disease (2005 and 2011, adapted)
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=931
  • Renal artery stenting with optimal medical therapy (OMT; n=459)
  • Optimal medical therapy (n=472)
• Median follow-up: 3.6 years
• Analysis: Intention-to-treat
• Primary outcome: CVD mortality, renal mortality, MI, stroke, HF hospitalization, worsening renal insufficiency, or need for RRT

Population

Inclusion Criteria

• Age ≥18 with severe renal artery stenosis defined by any of the following:
  • Angiography with stenosis >80% to <100%
  • Duplex with systolic velocity >300 cm/sec
  • MRA with one of the following:
    • Stenosis >80%
    • Stenosis >70% with contrast MRI and spin dephasing on 3D phase
    • Stenosis >70% and ≥2 of the following:
      • Ischemic kidney >1 cm smaller than other kidney
      • Ischemic kidney enhances less on arterial phase
      • Ischemic kidney with delayed excretion of gadolinium
      • Ischemic kidney hyper-concentrates the urine
      • 2D phase contrast flow with delayed systolic peak on waveform
      • Dilation following the stenosis
  • CTA with one of the following:
    • Stenosis >80%
    • Stenosis >70% and ≥2 of the following:
      • Ischemic kidney >1 cm smaller than other kidney
      • Reduced cortical thickness of affected kidney
      • Less cortical enhancement on arterial phase
      • Dilation following the stenosis
• ≥1 of these medical conditions:
  • Hypertension on ≥2 BP medications
  • CKD stage 3 or worse

Exclusion Criteria

• Fibromuscular dysplasia
• Chronic kidney disease from causes other than ischemic nephropathy
• Serum creatinine >354 mcmol/L (4.0mg/dL)
• Target kidney <7cm
• Lesions could not be treated with a single stent
• Allergy to medications in protocol
• Multiple renal arteries that might be relieving stenosis
• Artery <3.5 mm in diameter

Baseline Characteristics

From the stenting plus medical therapy group.

• Demographics: Age 69.3y, 51% male, 7% Black
• Anthropometrics: BMI 28.2 kg/m², SBP 150 mm Hg.
• Renal function: eGFR: 58 ml/min/1.73cm², 50% Stage ≥3 CKD
• Method of Stenosis Identification:
  • Angiography: 68%
  • Duplex ultrasonography: 25%
  • CT Angiography: 4%
  • MR Angiography: 2%
• Comorbidities: DM 32%, prior MI 26%, HF 12%, smoking in prior year 28%, hyperlipidemia 89%
• Angiographic findings:
  • % Stenosis by core lab: 67%
  • % Stenosis by investigator: 72%
  • Global ischemia: 20%
    • >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. NS is non-significant. Statistics only given when provided by authors.

Primary Outcome

CVD mortality, renal mortality, MI, stroke, HF hospitalization, worsening renal insufficiency, or need for RRT

35.1% vs. 35.8% (HR 0.94, 95% CI 0.76-1.17; P=0.58)

Components of the primary outcome were not primary outcomes but are included here for simplicity.

CVD mortality: 8.9 vs. 9.5% (HR 0.89; 95% CI 0.58-1.36)

Renal mortality: 0.4 vs. 0.2% (HR 1.89; 95% CI 0.17-20.85)

Stroke: 3.5 vs. 4.9% (HR 0.68; 95% 0.36-1.28)

MI: 8.7 vs. 7.8% (HR 1.09; 0.70-1.71)

HF hospitalization: 8.5 vs. 8.3% (HR 1.00; 95% CI 0.64-1.56)

Worsening renal insufficiency: 16.8 vs. 18.9% (HR 0.86; 95% CI 0.64-1.17)

Need for RRT: 3.5% vs. 1.7% (HR 1.98; 95% CI 0.85-4.62)

Secondary Outcomes

All-cause mortality

13.7 vs. 16.1% (HR 0.80; 95% CI 0.58-1.12)

Subgroup Analyses

There was no difference in the primary outcomes for creatinine level, gfr, diabetes, sex, global ischemia, race, baseline SBP, age, geographic location, and maximal diameter of the stensosis.

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)