The Hippocratic Oath which outlines the professional ethical standards of physicians includes the classic prohibition of “to do no harm”
Two trials of the management of atherosclerotic renal artery stenosis have been published recently.
First, the Dutch STAR trial randomised 140 patients to either medical therapy alone or medical therapy with renal artery stenting1. The entry criteria to the trial were impaired renal function (creatinine clearance <80 ml/min per 1.73m2), ostial renal artery stenosis established by any imaging modality and stable blood pressure. The reason for setting these eligibility criteria probably relate to the known morbidity and mortality of angiography (0–4%) with assessment of stenosis gradient as noted in previous prospective observational studies2,3 and higher rates (3–10%) from retrospective studies. Curiously the primary endpoint for the STAR trial was different for the two groups: Reduction of >20% of the estimated creatinine clearance for the medical therapy group and freedom from restenosis for the stented group. Although underpowered, the trial showed no difference in progression of renal disease between the groups. However there was significant morbidity and mortality in the stenting arm: Two patients died within 30 days of the procedure and one patient developed end-stage renal disease following an infected groin haematoma. Also 12/64 patients assigned to stenting had a renal artery stenosis of <50% at the time of the procedure. So this trial has been criticised for being underpowered and selecting the “wrong” patients.
The second trial to have been published was the larger ASTRAL trial, with over 800 patients randomised to either medical therapy alone or medical therapy and revascularisation4. Similar entry criteria as for the STAR trial prevailed and probably for similar reasons: refractory hypertension or renal dysfunction suggesting atherosclerotic renovascular disease and a substantial anatomical stenosis considered suitable for endovascular revascularisation on any suitable imaging study. Pressure gradients across the renal artery stenoses were not measured because there are no validated pressure gradient criteria for renal vessels and because of the concern that crossing a lesion with a catheter just to measure the gradient might damage the vessel or induce cholesterol emboli. Although pressure gradients can be categorised as more or less than 60% using duplex ultrasonography, this requires a very skilled vascular laboratory and the investigation fails in a significant proportion of people because of bowel gas, obesity or even aortic aneurysm. Therefore there would be real disadvantages to using duplex criteria for trial entry.
After a median of almost three years of follow-up there was no difference between the two randomised groups in the primary outcome measure, reciprocal of serum creatinine concentration (which is linearly related to creatinine clearance). Similarly there were no differences in the rates of either renal or cardiovascular events (secondary outcomes). This trial too has been criticised for selecting the “wrong” patients and for poor adherence to trial protocol (only 359/403 patients assigned to revascularisation underwent revascularisation (95% with stent) and 24/403 patients assigned to medical therapy only underwent revascularisation. However even the “per protocol” analysis (confined to the supplementary material4) did not provide any evidence in favour of revascularisation.
The critics did not point out either the number of procedure related events, at least 19 serious events in 17 patients (4.7%) or the increased proportion on ACE inhibitors in the revascularisation group4. These adverse events included myocardial infarction, pulmonary oedema, femoral artery aneurysm at puncture site, renal embolization with loss of renal function, distal embolization and infected haematomas resulting in extended hospital stay but no deaths. Renal artery stenosis often is considered as a contraindication to ACE inhibitors, but renal shut down is only likely in the presence of bilateral renal artery stenosis. On the other hand, ACE inhibitors are thought to have pleiotropic effects to reduce cardiovascular morbidity and mortality. However, there was no evidence that they helped patients in the revascularisation arm of the ASTRAL trial.
Criticisms also have been levelled at the requirement for clinicians to be in equipoise about treatment modality and benefit to randomise patients in the ASTRAL trial. Equipoise and pragmatism underscore the success of randomised trials. Both STAR and ASTRAL are examples of successful trials.
The purist trial, CORAL, is yet to report.5 This trial has measured renal artery stenosis as the entry criterion. The ASTRAL trial struggled with recruitment and had to extend the recruitment period and look to a few overseas centres. The extension of the CORAL trial to centres in Europe, South America and elsewhere also suggests struggling recruitment. This trial is not scheduled to report until 2011. Will the results of CORAL be more to the liking of aggressive endovascular interventionalists? Clearly they are pinning their hopes on favourable results for revascularisation in this trial. However, they too are unlikely to escape the punishment of adverse events after renal intervention.
Bearing in mind our Hippocratic Oath, all the evidence at the moment points to “do no harm”: The harms of revascularisation for atherosclerotic renal artery stenosis appear to outweigh the benefits. Well, there are no benefits for revascularisation so the harms far outweigh the benefits of medical therapy alone.
Janet Powell, Imperial College, London, UK
1 Bax L, Woittiez A-J J, Kouwenberg HJ et al. Stent placement in patients with atherosclerotic renal artery stenosis and impaired renal function. Ann Int Med 2009;150:840-8
2 Beutler JJ, Van Ampting JM, Van de Ven PJ et al. Long-term effects of arterial stenting on kidney function for patients with ostial atherosclerotic renal artery stensosis and renal insufficiency. J Am Soc Nephrol 2001;12:1475-81
3 Korsakas S, Mohaupt MG, Dinkel HP et al. Delay of dialysis in end-stage renal failure: prospective study onpercutaneous renal artery interventions. Kidney Int 2004;65:251-8
4 The Astral Investigators. Revascularization versus medical therapy for renal-artery stenosis. New Engl J Med 2009;361:1953-62
5 Cooper CJ, Murphy TP, Matsumoto A et al. Stent revascularization for the prevention of cardiovascular and renal events among patients with renal artery stenosis and systolic hypertension: rationale and design of the CORAL trial. Am Heart J 2006;152:59-66