Health Policy Advisory Committee on Technology

Health Policy Advisory Committee on Technology Technology Brief Stenting versus medical therapy for atherosclerotic renal artery stenosis April 2016

State of Queensland (Queensland Department of Health) 2016 This work is licensed under a Creative Commons Attribution Non-Commercial No Derivatives 3.0 Australia licence. In essence, you are free to copy and communicate the work in its current form for non-commercial purposes, as long as you attribute the authors and abide by the licence terms. You may not alter or adapt the work in any way. To view a copy of this licence, visit http://creativecommons.org/licenses/by-nc-nd/3.0/au/deed.en. For further information, contact the HealthPACT Secretariat at: HealthPACT Secretariat c/o Healthcare Improvement Unit, Clinical Excellence Division Department of Health, Queensland Level 2, 15 Butterfield St HERSTON QLD 4029 Postal Address: GPO Box 48, Brisbane QLD 4001 Email: HealthPACT@health.qld.gov.au Telephone: +61 7 3328 9180 For permissions beyond the scope of this licence contact: Intellectual Property Officer, Department of Health, GPO Box 48, Brisbane QLD 4001, email ip_officer@health.qld.gov.au, phone (07) 3328 9824. Electronic copies can be obtained from: http://www.health.qld.gov.au/healthpact DISCLAIMER: This Brief is published with the intention of providing information of interest. It is based on information available at the time of research and cannot be expected to cover any developments arising from subsequent improvements to health technologies. This Brief is based on a limited literature search and is not a definitive statement on the safety, effectiveness or costeffectiveness of the health technology covered. The State of Queensland acting through Queensland Health ( Queensland Health ) does not guarantee the accuracy, currency or completeness of the information in this Brief. Information may contain or summarise the views of others, and not necessarily reflect the views of Queensland Health. This Brief is not intended to be used as medical advice and it is not intended to be used to diagnose, treat, cure or prevent any disease, nor should it be used for therapeutic purposes or as a substitute for a health professional's advice. It must not be relied upon without verification from authoritative sources. Queensland Health does not accept any liability, including for any injury, loss or damage, incurred by use of or reliance on the information. This Brief was commissioned by Queensland Health, in its role as the Secretariat of the Health Policy Advisory Committee on Technology (HealthPACT). The production of this Brief was overseen by HealthPACT. HealthPACT comprises representatives from health departments in all States and Territories, the Australian and New Zealand governments and MSAC. It is a sub-committee of the Australian Health Ministers Advisory Council (AHMAC), reporting to AHMAC s Hospitals Principal Committee (HPC). AHMAC supports HealthPACT through funding. This Brief was prepared by Jacqueline Parsons and Benjamin Ellery from Adelaide Health Technology Assessment, University of Adelaide.

Summary of findings Early observational studies on stenting for renal artery stenosis showed promising results in terms of hypertension control and renal function, however the results have not been replicated in clinical trials. Recent meta-analyses including around 1,000 patients in each arm showed no benefit of angioplasty with stenting over medical therapy alone. These trials have been criticised for including patients with only mild and moderate disease; subgroup analyses on the groups with more severe disease has not been available to date. Despite a lack of trial evidence, there is still considerable support for the use of renal artery stenting in selected patient groups; namely those with flash pulmonary oedema, severe refractory hypertension or progressive decline in renal function. HealthPACT Advice Despite a lack of robust clinical evidence to support its use, stenting for renal artery stenosis was introduced into routine clinical practice to prevent the progression of chronic kidney disease. It was thought that stenting would lower blood pressure, and as a consequence prevent the development of adverse cardiovascular and renal events. The pivotal CORAL study demonstrated that renal artery stenting proffers no clinical benefit for patients with severe stenosis and that comprehensive, multifactorial medical therapy is the preferred treatment option in these patients. It should be noted, however, that renal artery stenting may be appropriate for use in patients with acute pulmonary oedema, severe refractory hypertension or progressive decline in renal function. The number of renal stenting procedures performed in Australia and New Zealand has markedly reduced in recent years, however clinical practice guidelines still support its use. HealthPACT does not support the use of renal artery stenosis for patients with severe stenosis in clinical practice and recommends these patients are treated with multifactorial medical therapy. However, renal artery stenting should remain a treatment option for patients with acute pulmonary oedema, severe refractory hypertension or progressive decline in renal function. HealthPACT recommends the relevant Australian and New Zealand clinical practice guidelines be amended to reflect this change in clinical practice. Stenting versus medical therapy for atherosclerotic renal artery stenosis: April 2016 i

Technology, Company and Licensing Register ID Technology name Patient indication Description of the technology WP207 Stenting versus medical therapy for atherosclerotic renal artery stenosis Patients with secondary hypertension caused by hardening and narrowing of the arteries supplying the kidneys Stenting for renal artery stenosis is an established technology. Where narrowed renal arteries are unable to be satisfactorily opened with balloon angioplasty, a stent may be used to maintain patency of the blood vessel. This is very similar to angioplasty and stent insertion in the cardiac arteries. Company or developer Various companies make stents and the accompanying equipment for angioplasty and stenting. Reason for assessment Recent research indicates that stenting for renal artery stenosis does not incur benefit, however it may be beneficial in certain patient indications. A summary of evidence is required for potential partial disinvestment from public health systems in Australia and New Zealand. Stage of development in Australia Yet to emerge Experimental Investigational Nearly established Established Established but changed indication or modification of technique Should be taken out of use Licensing, reimbursement and other approval Established technology. Technology type Technology use Procedure Therapeutic Patient Indication and Setting Disease description and associated mortality and morbidity Atherosclerotic renal artery stenosis (ARAS) is characterised by narrowing and hardening of the renal arteries, resulting in impaired blood flow to the kidneys. It is the most common Stenting versus medical therapy for atherosclerotic renal artery stenosis: April 2016 1

cause of secondary hypertension. The mechanism is well understood: reduced blood flow results in activation of the renin-angiotensin-aldosterone axis, which results in vasoconstriction, sodium and water retention, aldosterone secretion, sympathetic nervous system activation, vascular remodelling and resultant hypertension. 1 It is strongly associated with atherosclerosis in other parts of the body, and increases the chances of cardiovascular events, as well as contributing to decline in renal function and subsequent kidney failure. 2 One study found the risk ratio for patients with more than 50 per cent stenosis, compared to age-matched controls, to be 3.3 for overall mortality and 5.7 for cardiovascular mortality; another study found the overall mortality rate to be three times higher in patients with ARAS compared to patients without. 3 Interestingly, patients with ARAS are six to 28 times more likely to die of a cardiovascular event than to develop end-stage kidney disease (ESKD), although it is estimated that between two and 20 per cent of ESKD is caused by ARAS. 3 Kidney Health Australia estimate that 1.7 million Australians have chronic kidney disease, and 12 per cent of these cases are caused by hypertension. 4 ARAS is more common in older patients, and with the ageing of the population and widespread use of non-invasive screening tests, the prevalence of ARAS is likely to increase over time. 5 Number of patients Estimating the number of patients with ARAS and the number who undergo surgery for the condition is difficult as the location of the artery is not specified in Australian procedure data on angioplasty and stenting. The Australian Institute of Health and Welfare (AIHW) reported that atherosclerosis of the renal artery was the principal diagnosis in 387 episodes of hospital care in 2013-14. 6 Patients also experienced episodes of care for hypertensive kidney disease, hypertensive heart and kidney disease, and secondary hypertension, all of which could be related to ARAS (however details are not available). An American study found that the estimated prevalence of ARAS in the general population aged older than 65 years was seven per cent, but higher in patients with comorbidities; the estimated prevalence of ARAS was 20 per cent in patients with hypertension and diabetes, 25 per cent in patients with peripheral vascular disease and 54 per cent in patients with congestive heart failure. 3 Another study reported the prevalence of ARAS to be between two per cent (in unselected hypertensive patients) and 40 per cent (in older patients with atherosclerotic comorbidities). 7 It is estimated that ARAS is responsible for one to five per cent of all cases of hypertension. 5 A recent review noted a prevalence of ARAS of 0.5 per cent in the general population, seven per cent in the population over 65 years, up to 59 per cent in patients with peripheral arterial disease and 50 percent in patients with refractory congestive heart failure. 8 Speciality Technology setting Cardiovascular disease and vascular surgery General and specialist hospitals Stenting versus medical therapy for atherosclerotic renal stenosis: April 2016 2

Impact Alternative and/or complementary technology Renal artery stenting is used alongside balloon angioplasty and in conjunction with medical therapy for the control of hypertension in patients with ARAS. Diffusion of technology in Australia Established technology. International utilisation Country World wide Trials underway or completed Level of Use Limited use Widely diffused Cost infrastructure and economic consequences It is difficult to estimate the cost of renal artery stenting with the data available in the AIHW hospitals database, however percutaneous transluminal balloon angioplasty with insertion of a single stent, in vascular sites other than the coronary or carotid arteries, was recorded in 6,923 procedures in 2013-14, and insertion of multiple stents in 2,759 procedures. The Medicare rebate for transluminal balloon angioplasty of 1 peripheral artery or vein of 1 limb, percutaneous or by open exposure, excluding associated radiological services or preparation, and excluding aftercare is $515.35. There is no mention of stenting for arteries other than the coronary arteries in the item descriptors. Ethical, cultural, access or religious considerations As with any percutaneous transluminal balloon angioplasty procedure, it must be conducted in a setting with appropriate infrastructure (including imaging) and skilled physicians to minimise potential adverse events; these hospitals are likely to be in cities and larger regional centres, with rural and remote patients being required to travel for the procedure. Evidence and Policy Safety and effectiveness Revascularisation of the renal arteries accelerated in use in the 1990s, based on the positive results of case series and increase in the general availability of endovascular procedures. Other observational and experimental studies of revascularisation followed; however it was not until 2009 that trials specifically investigating the performance of renal artery stenting were reported. In 2014, the largest trial to date was published. Since then, many reviews and opinion pieces have been published, and two systematic reviews (SRs) were identified. These SRs (Level I Intervention evidence) are summarised below. Stenting versus medical therapy for atherosclerotic renal stenosis: April 2016 3

A Cochrane SR published in 2014 included only randomised controlled trials (RCTs) that compared the effectiveness of balloon angioplasty, with and without stenting, to medical therapy in patients with ARAS. 5 The review included studies where the patients had haemodynamically significant renal artery stenosis, defined as greater than 50 per cent reduction in luminal diameter, and hypertension (diastolic blood pressure 95mmHg). The outcomes of interest were blood pressure control, renal function, cardiovascular and renal adverse events (including death), occurrence of restenosis, side effects of medical therapy and use of antihypertensive drugs. The outcomes were reported after a minimum follow up of six months. In the eight included trials, there was a considerable difference in the proportion of patients who underwent stenting with their angioplasty; in the older trials (1998, 2005) between zero and nine per cent received a stent, and in the more recent trials (2009-2014) between 72 and 95 per cent of participants received a stent. The authors reported results of the five studies that used stenting as a subgroup analysis, and the results did not significantly change any of the results, apart from making the significant difference in diastolic blood pressure, seen in the overall analysis, no longer significant. The results from this subgroup are not reported; thus, the overall results are presented with the caveat that not all the studies included in each meta-analysis used stenting, but that this made little difference to the results. The authors reported that the overall quality of the evidence was moderate but variable, and noted that two trials contributed the majority of patients to the meta-analysis. Heterogeneity was low. The results of the meta-analyses are shown in Table 1. The authors concluded that there was insufficient evidence to conclude if revascularisation of the renal artery is superior to medical therapy in lowering blood pressure, nor in reducing the incidence of cardiovascular or renal adverse events. However angioplasty does appear to be safe. Importantly, they noted that none of the trials presented data separately according to the severity of the stenosis, and analyses to try and identify particular groups who may have benefit was not possible. 5 Stenting versus medical therapy for atherosclerotic renal stenosis: April 2016 4

Table 1 Results of meta-analysis of selected outcomes in revascularisation trials, as reported in Jenks et al (2014) 5 Outcome (measure) Number of trials Revascularisation (n) Medical Therapy (n) Result (95% CI) Change in systolic BP (mmhg) at 2 years or end of follow-up 5 857 886 MD -1.07 (-3.45, 1.30) Change in diastolic BP (mmhg) at 2 years or end of follow-up 4 397 412 MD -2.00 (-3.72, -.027)* Number of antihypertensive drugs 3 847 870 MD -0.18 (-0.34, -0.03)* Cardiovascular adverse events 7 1039 1071 OR 0.91 (0.75, 1.11) Renal adverse events 7 1036 1068 OR 1.02 (0.75, 1.38) Table notes: BP = blood pressure; MD = mean difference; OR = Peto odds ratio; * = favours revascularisation; note that all trials, including those that did not stent patients, were eligible for inclusion in the meta-analysis. Subgroup analysis (meta-analyses not reported) showed that the stenting trials made no significant difference to the results, except for the diastolic BP outcome which was not statistically significant in the stenting trials alone. A second SR also published in 2014 included seven RCTs, all of which were in the Cochrane review. 9 The trial not included was the trial prematurely terminated for which only preliminary data were available. This review used appropriate methods and appraised the risk of bias in the studies using the Cochrane tool. Not unexpectedly, the results were very similar to the Cochrane review, although this review conducted a meta-analysis on more specific outcome measures. Rather than cardiovascular adverse events as a whole, this review separated several cardiovascular endpoints, i.e. non-fatal myocardial infarction, congestive heart failure, and stroke, and considered all-cause mortality as a separate outcome. This review also presented the results for the stenting trials separately to the angioplasty-only trials. As with the Cochrane review, this review found stenting to be no better than medical therapy with respect to all-cause mortality, non-fatal myocardial infarction, stroke, systolic blood pressure, hospitalisation due to congestive heart failure or renal events. There was a small, statistically significant decrease in the number of antihypertensive medications in the stented group; the clinical significance of this reduction is not discussed. Results are presented in Table 2. The authors conclusions were similar to the Cochrane review, stating that revascularisation with stenting is not superior to medical therapy for ARAS. They also noted that the measurement of stenosis and heterogeneity in the degree of stenosis in patients in the trials was a limiting factor. 9 Stenting versus medical therapy for atherosclerotic renal stenosis: April 2016 5

Table 2 Results of meta-analysis of selected outcomes in revascularisation trials that used stenting, as reported in Riaz et al (2014) 9 Outcome (measure) Number of trials Result (95% CI) Non-fatal MI 4 OR 0.99 (0.69, 1.43) Number of antihypertensive drugs 1 5 MD -0.18 (-0.27, -0.09)* All cause mortality 4 OR 0.91 (0.72, 1.15) Stroke 4 OR 1.21 (0.72, 1.74) Congestive heart failure 3 OR 1.15 (0.84, 1.57) Renal events 4 OR 0.95 (0.76, 1.18) Table notes: BP = blood pressure; MD = mean difference; OR = Peto odds ratio; * = favours revascularisation; 1 meta-analysis included all revascularisation trials, not only stenting Thus, it is clear that in these meta-analyses, revascularisation with stenting is not superior to medical therapy on any outcome except the number of antihypertensive drugs used, and the clinical significance of that difference is questionable. However, the authors of both reviews note that limited information about the severity of stenosis and other clinical conditions affecting the patient was available, and investigation of particular subgroups has not occurred to date. The inclusion criteria of a selection of trials, reported in the Cochrane review, give some indication as to the heterogeneity of patient indications that participated in the trials. 5 The ASTRAL trial only included patients with uncontrolled or refractory hypertension, or unexplained renal dysfunction with evidence of substantial anatomical atherosclerotic stenosis in at least one renal artery and in whom the value of stenting was uncertain; thus, if the physician thought the patient would benefit from revascularisation, they were excluded from the study. This is likely to have been the more severe cases of stenosis. The CORAL trial included patients only with a stenosis of 80 to 90 per cent, or 60 to 70 per cent with a systolic pressure gradient of more than 20 mmhg, and elevated blood pressure or chronic kidney disease or both. They excluded patients with stenosis or kidney disease due to other causes and patients in whom they believed could not be treated with a single stent. However, the original enrolment criteria were relaxed during the trial due to slow recruitment, and patients without hypertension and chronic kidney disease were recruited. The STAR trial included patients with impaired renal function with stenosis of >50 per cent, but excluded patients with creatinine clearance of less than 15 ml/min, small renal diameter, small renal size, diabetes with proteinuria or malignant hypertension; again, likely to exclude the more severe cases. Stenting versus medical therapy for atherosclerotic renal stenosis: April 2016 6

It is worth mentioning that many of the reviews and opinion pieces that have been published on this topic believe that there is a place for stenting in ARAS with the correct patient indication. A review of the history of treatment for ARAS stated that even without definitive evidence, high-risk patients such as those with recurrent flash pulmonary oedema, rapidly declining kidney function or refractory hypertension may benefit from revascularisation. 8 Chrysant (2013) agreed that these were indications for significant ARAS and compelling reasons for intervention. 10 Another review reported that, in their practice, revascularisation is reserved for patients with severe and truly refractory hypertension that is failing aggressive medical management, patients with severe hypertension and declining renal function and patients with hypertensive emergency. This is despite recognising that trial data could not support or refute the effectiveness of revascularisation in severe ARAS. 11 Jennings et al also noted that there is likely to be a place for revascularisation in clinical care, but selecting the correct patients is difficult and there is currently no reliable method for identifying them, especially given that the degree of stenosis correlates poorly with outcomes. The authors conclude that revascularisation may be considered in patients who fail to stabilise with medical management or who present with multiple high risk features such as flash pulmonary oedema. 12 Australian authors Mohan and Bourke state that best evidence still supports intervention for patients with severe ARAS but do not offer that evidence; however they are strong in their assertion that the trials to date have only shown that stenting is no better than medical therapy in patients with moderately severe ARAS. 13 Likewise, Mousa (2015) stated that patients with pulmonary oedema without valvular or ischaemic substrate should be considered for stents, and patients with uncontrolled hypertension, deteriorating renal function, abrupt congestive heart failure or a combination of these should be referred for intervention; however noted that there is a lack of Level I data for any indication. 14 In summary, clinical trials have shown no added benefit of stenting over medical therapy in the general population of patients with ARAS; however, many participants in these trials had only moderate severity of disease and subgroup analyses of particular groups with more severe disease have not occurred to date. There is still considerable interest in renal artery stenting and its application in these groups. There does seem to be support for the use of revascularisation in patients with flash pulmonary oedema, severe refractory hypertension and progressive deterioration in renal function. Guidelines from around the world were consulted to check on their recommendations for the use of renal artery stenting. No relevant Australian guidelines were identified. Overall, the level of evidence supporting the guidelines for specific groups was low, as these groups have not been investigated in trials. Canadian hypertension guidelines do not recommend renal artery angioplasty and stenting, given that it offers no benefit over medical management. 15 However, the guidelines group Stenting versus medical therapy for atherosclerotic renal stenosis: April 2016 7

also noted that the trials are likely to have included patients with less severe stenosis, and given that the point estimates in the meta-analyses favoured angioplasty, it is possible that it could be useful in patients with severe or refractory hypertension. They recommended that it could be considered in patients with uncontrolled hypertension resistant to maximally tolerated pharmacotherapy, progressive renal function loss, and acute pulmonary edema. 15 The Society for Cardiovascular Angiography and Interventions Consensus Statement for Renal Artery Stenting Appropriate Use published in 2014 recommended that renal artery stenting represents appropriate care in patients with flash pulmonary oedema, severe bilateral ARAS or stenosis to a solitary functioning kidney, accelerated or resistant hypertension, progressive deterioration in renal function and global renal ischaemia. 1 The procedure rarely represents appropriate care in patients with haemodynamically mild to moderate stenosis. Although these recommendations mentioned multisocietal guidelines with evidence levels, these levels are not explained, so it is difficult to ascertain what they pertain to and whether the evidence for these recommendations is robust. European Cardiac Society guidelines, last published in 2011, also recommend angioplasty with stenting in some patients with more severe ARAS. 16 Their recommendations were based on three levels of evidence: Level A, supported by multiple RCTs or meta-analyses; Level B, supported by data derived from a single RCT or large non-randomised studies; and, Level C, consensus of opinion of experts and/or small studies, retrospective studies or registries. These were combined with class of recommendation; ranging from Class I, recommended or indicated; Class IIa and IIb, should be and may be considered; and, Class III, not recommended. Stenting is recommended in patients with ostial stenosis (Level B), and may be considered in patients with symptomatic ARAS with stenosis of more than60 per cent (Level A), patients with impaired renal function (Level B) and patients with ARAS and unexplained recurrent congestive heart failure or sudden pulmonary oedema and preserved left systolic ventricular function (Level C). 16 It should be noted that these guidelines were published before the release of the results from the CORAL trial. The American College of Cardiology Foundation and American Heart Association Task Force on Practice Guidelines (2013) used the same Level and Class rating system as described above. 17 These guidelines state that indications for revascularisation are: asymptomatic bilateral or solitary viable kidney with haemodynamically significant ARAS (Level C, Class IIb); haemodynamically significant ARAS and accelerated, resistant or malignant hypertension (Level B, Class IIa); bilateral ARAS or ARAS in a solitary functioning kidney and progressive chronic kidney disease (Level B, Class IIa); patients with chronic renal insufficiency with unilateral ARAS (Level C, Class IIa); patients with haemodynamically significant ARAS and recurrent, unexplained congestive heart failure or sudden pulmonary oedema (Level B, Class I); and, patients with haemodynamically significant ARAS and unstable angina (Level B, Class Stenting versus medical therapy for atherosclerotic renal stenosis: April 2016 8

IIa). Stent insertion is indicated for ostial ARAS lesions that meet the clinical criteria for intervention (Level B, Class I). 17 Again, these guidelines have not been informed by the most recent trial data. Economic evaluation No recent economic evaluations of renal artery stenting were identified; however it should be noted that this Brief is not a systematic review and therefore information about this aspect of the procedure could have been missed. Even older economic evaluations were limited and tended to focus on diagnosis of ARAS rather than treatment, and so have not been considered here. As yet, the procedure has not appeared on the Choosing Wisely list in the United States nor on the UK s National Institute of Health and Care Excellence (NICE) do not do list. Ongoing research A search of ClinicalTrials.gov for RCTs comparing stenting with medical therapy revealed an RCT of similar design to the previous trials (NCT01208714); eligible patients have clinical or radiological evidence of unilateral or bilateral renal atherosclerotic stenosis, defined by stenosis of the proximal portions of the renal artery and its main bifurcations at angioct (angio-computed tomography). This trial is being conducted in Italy, however its status is recorded as not yet open for recruitment, despite it being due for completion in 2016. A second RCT in France (NCT02539810) is currently recruiting participants with officemeasured blood pressure of at least 140 mmhg systolic and/or 90 mmhg diastolic despite a stable medication regime including full tolerated doses of three or more anti-hypertensive treatments of different classes, and unilateral or bilateral ARAS of at least60 per cent. Two other trials of stenting versus medical therapy have unknown status as they have not been recently updated: NCT00711984 and NCT01173666. No relevant trials were identified on the Australian and New Zealand Clinical Trial Registry (ANZCTR). Other issues None identified. Number of studies included All evidence included for assessment in this Technology Brief has been assessed according to the revised NHMRC levels of evidence. A document summarising these levels may be accessed via the HealthPACT web site. Total number of studies: 2 Total number of Level I studies: 2 Stenting versus medical therapy for atherosclerotic renal stenosis: April 2016 9

Search criteria to be used (MeSH terms) Renal artery stenosis (text) MeSH: renal artery obstruction References 1. Parikh, S. A., Shishehbor, M. H. et al (2014). 'SCAI expert consensus statement for renal artery stenting appropriate use'. Catheter Cardiovasc Interv, 84 (7), 1163-71. 2. Weber, B. R.& Dieter, R. S. (2014). 'Renal artery stenosis: epidemiology and treatment'. Int J Nephrol Renovasc Dis, 7, 169-81. 3. Yu, M. S., Folt, D. A. et al (2014). 'Endovascular versus medical therapy for atherosclerotic renovascular disease'. Curr Atheroscler Rep, 16 (12), 459. 4. Kidney Health Australia (2015). Chronic Kidney Disease Management in General Practice, Kidney Health Australia, Melbourne, Vic http://www.kidney.org.au/healthprofessionals/prevent/chronic-kidney-disease-management-handbook. 5. Jenks, S., Yeoh, S. E.& Conway, B. R. (2014). 'Balloon angioplasty, with and without stenting, versus medical therapy for hypertensive patients with renal artery stenosis'. Cochrane Database Syst Rev, 12, CD002944. 6. Australian Institute of Health and Welfare (2016). Separation statistics by principal diagnosis in ICD-10-AM, Australia, 2013-14. [Internet]. AIHW. Available from: http://www.aihw.gov.au/hospitals-data/principal-diagnosis-data-cubes/ [Accessed 3 Feb 2016]. 7. Martinelli, O., Malaj, A. et al (2015). 'Stenting Versus Medical Treatment for Renal Atherosclerotic Artery Stenosis'. Angiology, 66 (3), 201-3. 8. Bohlke, M.& Barcellos, F. C. (2015). 'From the 1990s to CORAL (Cardiovascular Outcomes in Renal Atherosclerotic Lesions) trial results and beyond: does stenting have a role in ischemic nephropathy?'. Am J Kidney Dis, 65 (4), 611-22. 9. Riaz, I. B., Husnain, M. et al (2014). 'Meta-analysis of revascularization versus medical therapy for atherosclerotic renal artery stenosis'. Am J Cardiol, 114 (7), 1116-23. 10. Chrysant, S. G. (2013). 'The current status of angioplasty of atherosclerotic renal artery stenosis for the treatment of hypertension'. J Clin Hypertens (Greenwich), 15 (9), 694-8. 11. Corriere, M. A.& Edwards, M. S. (2013). 'Results of the major randomized clinical trials of renal stenting and implications for future treatment strategies'. Semin Vasc Surg, 26 (4), 161-4. 12. Jennings, C. G., Houston, J. G. et al (2014). 'Renal artery stenosis-when to screen, what to stent?'. Curr Atheroscler Rep, 16 (6), 416. 13. Mohan, I. V.& Bourke, V. (2015). 'The management of renal artery stenosis: an alternative interpretation of ASTRAL and CORAL'. Eur J Vasc Endovasc Surg, 49 (4), 465-73. 14. Mousa, A. Y., AbuRahma, A. F. et al (2015). 'Update on intervention versus medical therapy for atherosclerotic renal artery stenosis'. J Vasc Surg, 61 (6), 1613-23. Stenting versus medical therapy for atherosclerotic renal stenosis: April 2016 10

15. Daskalopoulou, S. S., Rabi, D. M. et al (2015). 'The 2015 Canadian Hypertension Education Program Recommendations for Blood Pressure Measurement, Diagnosis, Assessment of Risk, Prevention, and Treatment of Hypertension'. Canadian Journal of Cardiology, 31 (5), 549-68. 16. Tendera, M., Aboyans, V. et al (2011). 'ESC Guidelines on the diagnosis and treatment of peripheral artery diseases: Document covering atherosclerotic disease of extracranial carotid and vertebral, mesenteric, renal, upper and lower extremity arteries: the Task Force on the Diagnosis and Treatment of Peripheral Artery Diseases of the European Society of Cardiology (ESC)'. Eur Heart J, 32 (22), 2851-906. 17. Anderson, J. L., Halperin, J. L. et al (2013). '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'. Journal of the American College of Cardiology, 61 (14), 1555-70. Stenting versus medical therapy for atherosclerotic renal stenosis: April 2016 11