ASTRAL

Published

Wheatley K, et al. "Revascularization versus medical therapy for renal-artery stenosis". The New England Journal of Medicine. 2009. 361(20):1953-1962.
PubMed • Full text • PDF

Clinical Question

Among patients with renal artery stenosis not clearly requiring revascularization, how well does endovascular revascularization preserve renal function when compared to medical therapy alone?

Bottom Line

Treatment of renal artery stenosis with endovascular revascularization and medical therapy did not preserve renal function when compared to medical therapy alone. Generalizability of this outcome is limited as patients who were deemed to likely benefit from revascularization were excluded.

Major Points

Renal artery stenosis (RAS) often results in progressive renal dysfunction. No large trial had demonstrated efficacy of revascularization plus medical therapy to medical therapy alone in prevention of this outcome.

The 2009 Angioplasty and Stenting for Renal Artery Lesions (ASTRAL) trial randomized 806 patients with RAS that would not clearly benefit from revascularization to either endovascular revascularization with medical therapy or medical therapy alone. Though the median follow-up was 34 months, the authors' primary outcome was a surrogate for renal function over 5 years (slope of the reciprocal of creatinine). There was no significant difference between the groups. Both groups had reduction in BP though the medical therapy group had greater reduction in DBP. There was no difference in survival. Revascularization procedures had a 9% periprocedural complication rate, about half of which were considered serious.

This trial has been criticized for low rate of medications affecting RAAS and lack of functional assessment of the degree of stenosis (similar to FFR in CAD with FAME and FAME 2). However, no randomized trial has evaluated optimal medical therapy in this disease and the use of ACE-inhibitors or ARBs are fraught with complications including precipitation of significant renal dysfunction. Despite this risk, ACE-inhibitor use is associated with reduction in CV events and mortality. Outdated guidelines from the AHA recommend ACE-inhibitors (level 1A), ARBs (level 1B), CCBs (level 1A), and beta blockers (level 1A) in this disease for treatment of unilateral RAS. Thus, the treatment of RAS remains controversial.

Of note, patients with RAS experience a higher rate of coronary events, an endpoint that ASTRAL was not powered to measure. The CORAL trial subsequently published in 2014 found no difference in cardiovascular and renal outcomes with stenting, although limitations of this trial may still prevent generalizability of the study's results to all patients with RAS. A 2015 Cochrane review concluded balloon angioplasty (with or without stenting) conferred no benefit in cardiovascular or renal outcomes. The intervention was associated with a modest reduction in DBP and number of antihypertensive medications needed.

Guidelines

K/DOQI Hypertension and Antihypertensive Agents in Chronic Kidney Disease

• For patients in whom there is a clinical suspicion of RAD, the clinician should do one or more of the following:
  1. Estimate the probability of RAD using a predictive index derived from clinical characteristics (B)
  2. Obtain a noninvasive screening test for RAD (A)
  3. Refer to a kidney disease or hypertension specialist for evaluation (C).
• Patients found to have hemodynamically significant RAD should be referred to a kidney disease or hypertension specialist for management (C).
• There is insufficient evidence to prefer one of the variety of options for revascularization versus medical therapy.

ACC/AHA Management of peripheral arterial disease (2005 and 2011, adapted)

• 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 (Class IIb, 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)

2017 ACC AHA AAPA ABC ACPM AGS APhA ASH ASPC NMA PCNA Hypertension (2017, adapted)

• Medical therapy is recommended in RAS (COR I, LOE A)
• Among adults who failed medical management and those with non-atherosclerotic disease (e.g., FMD), it may be reasonable to refer for consideration of revascularization with angioplasty or a stent (COR IIb, LOE C-EO)

Design

• Multicenter, randomized, controlled, open-label trial
• N=806
  • Revascularization (n=403)
  • Medical therapy (n=403)
• Setting: 57 hospitals in the UK, Australia, and New Zealand
• Enrollment: 2000-2007
• Median follow-up: 34 months
• Analysis: Intention-to-treat
• Primary outcome: Slope of the reciprocal of creatinine over 5 years

Population

Screening Criteria

Clinical findings suggestive of RAS like uncontrolled HTN, refractery HTN, or unexplained renal dysfunction.

Inclusion Criteria

• Renal artery atherosclerotic disease in ≥1 renal artery amenable to revascularization
• Clinician unsure if revascularization would provide clear benefit

Exclusion Criteria

• Disease necessitating surgical revascularization
• "High likelihood" of needing revascularization in the following 6 months
• Non-atheromatous cardiovascular disease
• Prior RAS revascularization
• Lack of informed consent

Baseline Characteristics

From the revascularization group except where specified. SI unit conversions calculated by WJC editor.

• Demographics: Age 70 years, male 63%
• PMH: DM 31%, CAD 50%, PVD 41%, stroke 18%, active smoker 20% (former 51%)
• Renal data:
  • Creatinine: 179 umol/L (2.02 mg/dL)
    • <150 umol/L (<1.7 mg/dL): 40%
    • 150-300 umol/L (1.7-3.39 mg/dL): 53%
    • >300 umol/L (>3.39 mg/dL): 7%
    • Rapid increase: 12% (rise >20% or >100 umol/L or >1.13 mg/dL in 1 year)
  • GFR: 40.3 mL/min
    • <25 mL/min: 22%
    • 25-50 mL/min: 53%
    • >50 mL/min: 25%
  • Urine protine: 0.55 g/day
  • Stenosis: 76%
    • <50%: 2%
    • 50-70%: 39%
    • >70%: 60%
  • Kidney length: 9.7 cm
• Medications:
  • Antihypertensives: 97% (diuretic 70%, CCB 61% revascularization vs. 68% medical therapy (P=0.05), beta-blocker 46%, ACE-inhibitor or ARB 47% revascularization vs. 38% medical therapy (P=0.02), alpha-blocker 39%)
    • Number of antihypertensives: 2.79
  • Antiplatelet: 76% (ASA 91%)
  • Cholesterol: 80% (statin 96%)
  • Warfarin: 11%
• Other health data: BP 149/76 mmHg, Tchol 4.7 mmol/L (183 mg/dL)

Interventions

• Patients meeting the screening criteria had relevant labwork performed along with renal artery imaging with intraarterial imaging, CTA, or MRA; those meeting inclusion and no exclusion criteria were randomized to a group:
  • Revascularization - Angioplasty +/- stenting within a goal of 4 weeks with medical therapy
  • Medical therapy - Medical therapy alone
• Medical therapy was defined by local practices though the authors state that this typically consisted of statins, antiplatelets, and blood pressure to goal ranges

Outcomes

Presented as revascularization vs. medical therapy except where stated.

Primary Outcome

Slope of the reciprocal of creatinine over 5 years

-0.07x10^-3 vs. -0.13x10^-3 L/umol (Favoring revascularization; 95% CI -0.002 to +0.013; P=0.06)

Per-protocol: No difference between groups

Secondary Outcomes

Mean reciprocal of creatinine over 5 years

0.09x10^-3 L/umol higher in revascularization group (95% CI -0.02 to +0.20 x10^-3 L/umol; P=0.10)

Mean serum creatinine over 5 years

SI conversion provided by the article's authors.

1.6 umol/L lower in revascularization group (95% CI -8.4 to +5.2 umol/L; P=0.64)

0.02 mg/dL lower in revascularization group (95% CI -0.10 to +0.06 mg/dL; P=0.64)

Slope of BP over 5 years

Systolic: Decreasing in both groups without between-group difference

Diastolic: Greater decrease in medical therapy group, diverging at 0.61 mmHg/year (95% CI 0.07 to 1.16; P=0.03)

Change in mean BP at 5 years

Systolic: 1.6 mmHg greater reduction in revascularization group (95% CI -3.21 to +0.08 mmHg; P=0.06)

Diastolic: Greater reduction in medical therapy group

Survival

No difference

Deaths: 103 vs. 106 events

Additional Analyses

Intervention attempted in revascularization group

83%

Successful intervention: 95%

Time to intervention: 32 days

Medical group that crossed over

6%

Time to intervention: 601 days

Subgroup Analysis

No differences in the primary outcome for predefined groups including baseline serum creatinine, GFR, RAS disease severity, length of kidney, or rate of renal impairment. Post-hoc analyses were likewise without significant difference including severe and non-severe anatomical disease.

Adverse Events

Renal events

New AKI, intiation of HD, renal transplant, nephrectomy, or renal mortality. Included are 383 and 392 patients with ≥1 follow-up assessment, excluding a patient with RCC-related nephrectomy.

73 events in 57 patients vs. 80 events in 58 patients (P=0.97)

Time to first event: No difference (HR 0.97; 95% CI 0.67-1.40; P=0.88)

AKI: 7% vs. 6%

ESRD: 8% vs. 8%

Major CV events

MI, stroke, CV mortality, angina hospitalization, volume overload/heart failure, coronary revascularization, or peripheral arterial procedure.

238 events in 141 patients vs. 244 events in 145 patients (P=0.96)

Procedural complications undergoing revascularization

Periprocedurally: 9% (31 of 359 patients)

Of note, one patient included above crossed over from the medical therapy group.

Serious: 19 events in 17 patients

Serious, at any time: 31 events in 23 patients

Criticisms

• Generalizability limited given enrollment only if the screening clinician did not think that the patient would clearly derive benefit from revascularization
• Low power to detect differences in subgroups
• Low rate of enrollment per site likely introduced selection bias
• Rate of serious complications was much higher than that reported in the literature and may be related to inexperienced practitioners (this claim was discounted by the authors)
• Lower overall number of antihypertensives prescribed to the intervention group may have masked the true benefit of revascularization
• No reporting of the renal-resistance index in those with high-grade stenoses
• Serum creatinine, used in the primary outcome, is only a surrogate for renal function
• Patients who would likely not benefit from revascularization (those with kidneys <6cm and those with "insignificant vascular lesions") were included in the trial
• Lower rate of RAAS-inhibiting medications than is recommended in clinical practice for those with RAS
• Diagnosis of RAS was made with noninvasive imaging without functional studies (like digital subtraction angiography) to determine severity of stenosis

Funding

• Medical Research Council UK
• Kidney Research UK
• Medtronic
• Authors with multiple financial disclosures