Journal of Human Hypertension (2007) 21, 511–515
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ORIGINAL ARTICLE
Angioplasty and STent for Renal Artery
Lesions (ASTRAL trial): rationale, methods
and results so far
S Mistry, N Ives, J Harding, K Fitzpatrick-Ellis, G Lipkin, PA Kalra, J Moss and K Wheatley
on behalf of the ASTRAL Collaborative Group
Birmingham Clinical Trials Unit, University of Birmingham, Edgbaston, Birmingham, UK
Atherosclerotic renovascular disease (ARVD) is a relatively common condition which may lead to progressive
renal dysfunction, and eventually to end-stage renal
failure. Revascularization has been used in an attempt to
prevent progression of ARVD, despite a lack of evidence
for a benefit on kidney function. Therefore, large-scale
randomized trials are needed to determine reliably
whether or not there is any worthwhile benefit. The
Angioplasty and STent for Renal Artery Lesions (ASTRAL) trial comparing renal function in ARVD patients
randomized to either revascularization or medical management alone was designed to provide this evidence.
ASTRAL started recruiting in November 2000 and, as of
the end of 2006, 731 patients have been randomized into
the trial (19 patients short of its minimum target of 750
patients). A pooled analysis (not split by treatment arm)
of all patients shows that serum creatinine increased
in the first 6 months then remained relatively steady,
whereas blood pressure has decreased from baseline.
The trial is due to close to recruitment in April 2007, with
the first presentation of the results of the randomized
treatment comparison planned for the spring of 2008.
To date ASTRAL is by far the largest randomized trial in
ARVD, and will provide the most reliable and timely
evidence on the role, if any, of revascularization in ARVD
with which to guide the treatment of future patients.
Journal of Human Hypertension (2007) 21, 511–515;
doi:10.1038/sj.jhh.1002185; published online 22 March 2007
Keywords: ASTRAL; RCT; ARVD; revascularization; renal dysfunction
Background and rationale
Atherosclerotic renovascular disease (ARVD) is a
relatively common condition in which proximal
atherosclerotic narrowing of the renal arteries may
lead to progressive renal dysfunction, and eventually to end-stage renal failure. Thus, the identification of an intervention that can delay, or even
prevent, the decline in renal function is of medical
importance.
One method used to attempt to prevent progression of ARVD, and hopefully, also, progressive
decline in renal function, is revascularization
usually by balloon angioplasty with stent insertion,
or by primary stenting. However, whilst there is
evidence showing that revascularization improves
arterial patency,1 there is currently no good evidence
to suggest that this translates into a benefit in terms
of renal function.2–3 To date, there have been three
published randomized trials comparing angioplasty
and medical management in hypertensive patients:4–6
Correspondence: S Mistry, Birmingham Clinical Trials Unit,
University of Birmingham, Park Grange, 1 Somerset Road,
Edgbaston, Birmingham B15 2RR, UK.
E-mail: [email protected]
Received 2 February 2007; revised 9 February 2007; accepted 9
February 2007; published online 22 March 2007
all were small and none were powered to investigate
adequately the effects of revascularization upon
renal function. A meta-analysis of data from these
trials suggested that whilst revascularization was
unlikely to provide a large treatment benefit on renal
function, it remained possible that it could have a
moderate, and clinically worthwhile, benefit, and
thus there was a need for further large-scale, longterm randomized evidence.3 The Angioplasty and
STent for Renal Artery Lesions (ASTRAL) trial was
designed to provide this evidence.
Trial design
The overall design of the ASTRAL trial is shown in
Figure 1. ASTRAL is jointly funded by the Medical
Research Council and Kidney Research UK, with
previous support from Medtronic AVE. The trial was
designed to be simple and pragmatic with minimum
paperwork and no extra clinic visits or tests beyond
those required in routine clinical practice. The trial
originally aimed to recruit 1000 patients over
5 years, with patients randomized equally between
revascularization (with medical therapy) and medical therapy alone. This sample size allowed for
more patient cross-over and patient mortality or loss
to follow-up than has actually occurred within the
ASTRAL trial of revascularization in ARVD patients
S Mistry et al
512
Diagnosis of ARVD (unilateral or bilateral)
Revascularization not contraindicated
Uncertain whether to revascularize
INFORMED CONSENT
&
RANDOMIZATION
Revascularization
with angioplasty and/or stent insertion
(and medical treatment)
No Revascularization
Medical treatment only
Follow-up at 1-3 months, 6-8 months, 1 year,
then annually
Renal function
Blood Pressure
Renal and vascular events
Mortality
Figure 1 Design of the ASTRAL trial.
Table 1 Primary and secondary end points in ASTRAL
Primary end point
Secondary end points
Rate of progression of renal
dysfunction (using serum
creatinine analysed by
reciprocal creatinine plots
over time)
Blood pressure control
Renal events (such as acute renal
failure, dialysis, transplant or
nephrectomy)
Serious vascular events (such
as myocardial infarction, angina
or stroke)
Mortality
Abbreviations: ASTRAL, Angioplasty and STent for Renal Artery
Lesions.
trial, so the sample size was subsequently reduced
to a minimum of 750 patients, which will give 80%
power to detect a moderate 20% reduction in rate of
decline of renal function as assessed by reciprocal
serum creatinine over time. The primary measure of
treatment efficacy is the rate of decline of renal
function over time (measured using serum creatinine), which will be compared between the two
treatment groups. The primary and secondary end
points of the trial are given in Table 1.
Criteria for entry
Patients are eligible for ASTRAL provided that:
They have had at least one ARVD lesion that
is suitable for balloon angioplasty and/or stent.
Journal of Human Hypertension
This must be confirmed by intra-arterial angiography, magnetic resonance angiography or computerized tomography.
They have not previously undergone a revascularization procedure for ARVD.
The medical team responsible for the patient’s
care is substantially uncertain about whether
early revascularization is clinically indicated. In
particular, it should be unlikely that revascularization will become definitely indicated within
the next 6 months.
These broad eligibility criteria mean that a
clinically relevant heterogeneous population has
been recruited into the trial. Thus as well as
determining an overall treatment effect, ASTRAL
will also provide the opportunity to investigate the
treatment effect in different types of patients (e.g. by
degree of renal dysfunction or severity of stenosis).
Randomization and follow-up
Eligible patients are randomized to either revascularization (which should be performed as soon as
possible, ideally within about 4 weeks of randomization) or medical therapy, with follow-up assessments at 1–3 months, 6–8 months and 1 year after
randomization, then annually thereafter.
Cardiac substudies
During the ASTRAL trial, two cardiac substudies
have commenced. ARVD patients have a high
cardiovascular mortality; they sometimes present
with heart failure, and recent reports indicate a
ASTRAL trial of revascularization in ARVD patients
S Mistry et al
513
much higher prevalence of cardiac structural and
functional abnormalities in these patients than in
those with chronic kidney disease of other aetiology.7 Systematic study of the effects of renal
intervention upon the heart has never previously
been undertaken, so assessment of whether or not
renal revascularization in patients with ARVD leads
to significant improvements in cardiac structure and
function is an important question. One sub-study is
assessing these parameters with echocardiography
(sample size 150 patients) and the other with cardiac
MR imaging (sample size 68 patients), the latter
being funded by the British Heart Foundation.
Progress so far
ASTRAL started recruiting in November 2000 and,
as of the end of December 2006, 731 patients have
been randomized into the trial of these 110 patients
have been entered into the echocardiographic substudy (recruitment commenced in January 2004) and
32 into the MR substudy (recruitment commenced
in July 2005). This means that ASTRAL is by far
the largest trial in ARVD, and is seven times bigger
than the previous largest reported trial (which
recruited 106 patients).6 Fifty-six centres have
entered patients into the trial, including three
centres in Australia and another in New Zealand.
ASTRAL is currently recruiting at the rate of
10 patients per month, and with recruitment due
to finish at the end of April 2007, the target of at
least 750 patients will be reached.
Baseline data show that an appropriately heterogeneous group of patients is being entered into
ASTRAL (Table 2). The mean age of patients at
randomization is 70 years and 62% are male. The
mean serum creatinine at baseline is 181 mmol/l,
mean blood pressure is 151/77 mm Hg, 54% are
ex-smokers, 19% are current smokers, 49% have a
history of coronary heart disease, 41% have a
history of peripheral vascular disease, 29% are
diabetic and 19% have a history of stroke.
Pooled analyses (based on 656 patients), not split
by treatment arm, of the mean change over time in
serum creatinine and blood pressure have been
performed. Initially, serum creatinine increased in
the first 6 months then remained relatively steady
(Figure 2), whereas both systolic and diastolic blood
pressures have shown some decreases from baseline
(Figure 3).
Patients with ARVD are at increased risk of acute
renal failure and major vascular events (e.g. stroke
and myocardial infarction). Assessing the impact
of revascularization on these types of events is a
secondary outcome in the trial. Five hundred and
forty-six patients have completed at least one
follow-up assessment (average length of follow-up
is nearly 2 years). Twenty-seven (5%) patients have
suffered acute renal failure, 46 (8%) patients have
commenced dialysis, 38 (7%) patients have had a
Table 2 Baseline characteristics of patients randomized into
ASTRAL
Mean age (range)
% Male
Mean weight (range)
Mean serum creatinine (range)
Mean blood pressure (range)
Mean cholesterol (range)
70 years (42–88)
62%
77 kg (40–125)
181 mmol/l (66–750)
151/77 (88/46–270/130)
4.7 mmol/l (0.1–10)
Abbreviations: ASTRAL, Angioplasty and STent for Renal Artery
Lesions.
Figure 2 Mean change in serum creatinine (mmol/l) over time (pooled analysis of patients randomized to revascularization and medical
management; error bars ¼ 95% confidence interval of the mean).
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ASTRAL trial of revascularization in ARVD patients
S Mistry et al
514
Figure 3 Mean change in blood pressure (mm Hg) over time (pooled analysis of patients randomized to revascularization and medical
management).
myocardial infarction, 40 (7%) patients have experienced angina, 26 (5%) patients have had a stroke, 33
(6%) patients have developed cancer and 96 (18%)
patients have died, with the commonest causes of
death being cardiac failure, cancer, renal failure and
pneumonia.
With ASTRAL due to complete recruitment in
April 2007, the first presentation of the results of the
randomized comparison is planned for the spring of
2008 (after the last patient entered into the trial has
been followed-up for at least 6 months). However, in
order that the long-term effects of revascularization
compared to medical management can be determined, patients within the ASTRAL trial will be
followed-up for at least 5 years.
Astral Management Committee
Colin Baigent, Susan Carr, Nick Chalmers, David
Eadington, Kate FitzPatrick-Ellis, Richard Gray,
George Hamilton, Jan Harding, Natalie Ives, Philip
Kalra, Graham Lipkin, Smitaa Mistry, Jon Moss,
Anthony Nicholson, John Scoble and Keith Wheatley.
Acknowledgements
We thank all the collaborators who have entered
patients into the ASTRAL trial and the patients who
have agreed to take part in the trial.
References
ASTRAL and other randomized trials
There have been no further published reports of
randomized trials of revascularization for ARVD
since ASTRAL opened. The STAR trial in the
Netherlands has recently finished accrual, but this
is a small trial of only about 140 patients, which will
also present its results (minimum follow-up 2 years)
in the spring of 2008. The CORAL trial in the USA
will address a similar question to ASTRAL and aims
to recruit 1000 patients.8 However, this trial is
specifically for patients with hypertension and
ARVD, so will not produce results that are as
generalizable as those from ASTRAL. Furthermore,
CORAL only commenced recruitment in early 2005,
and so it will be several years before the results are
likely to be reported. Hence, the ASTRAL trial will
provide the most reliable and timely evidence on the
role, if any, of revascularization in ARVD with
which to guide the treatment of future patients.
Journal of Human Hypertension
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