The Medical and Endovascular Treatment of Atherosclerotic Renal Artery Stenosis (METRAS) study: rationale and study design

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1 (2012) 26, & 2012 Macmillan Publishers Limited All rights reserved /12 ORIGINAL ARTICLE The Medical and Endovascular Treatment of Atherosclerotic Renal Artery Stenosis (METRAS) study: rationale and study design GP Rossi 1, TM Seccia 1, D Miotto 2, P Zucchetta 3, D Cecchin 3, L Caló 1, M Puato 1, R Motta 2, P Caielli 1, M Vincenzi 2, G Ramondo 2, S Taddei 4, C Ferri 5, C Letizia 6, C Borghi 7, A Morganti 8 and AC Pessina 1, on behalf of the METRAS Investigators 1 Department of DMCS Internal Medicine 4, Padova, Italy; 2 Institute of Radiology, Department of Medical-diagnostic Sciences, Padova, Italy; 3 Department of Nuclear Medicine, Padova, Italy; 4 Department of Internal Medicine, Pisa, Italy; 5 Department of Internal Medicine, L Aquila, Italy; 6 Department of Internal Medicine, Roma, Italy; 7 Department of Internal Medicine, Bologna, Italy and 8 Department of Internal Medicine, Milan, Italy It is unclear whether revascularization of renal artery stenosis (RAS) by means of percutaneous renal angioplasty and stenting (PTRAS) is advantageous over optimal medical therapy. Hence, we designed a randomized clinical trial based on an optimized patient selection strategy and hard experimental endpoints. Primary objective of this study is to determine whether PTRAS is superior or equivalent to optimal medical treatment for preserving glomerular filtration rate (GFR) in the ischemic kidney as assessed by 99mTcDTPA sequential renal scintiscan. Secondary objectives of this study are to establish whether the two treatments are equivalent in lowering blood pressure, preserving overall renal function and regressing target organ damage, preventing cardiovascular events and improving quality of life. The study is designed as a prospective multicentre randomized, un-blinded two-arm study. Eligible patients will have clinical and angio CT evidence of RAS. Inclusion criteria is RAS affecting the main renal artery or its major branches either 470% or, if o70, with post-stenotic dilatation. Renal function will be assessed with 99mTc-DTPA renal scintigraphy. Patients will be randomized to either arms considering both resistance index value in the ischemic kidney and the presence of unilateral/bilateral stenosis. Primary experimental endpoint will be the GFR of the ischemic kidney, assessed as quantitative variable by 99TcDTPA, and the loss of ischemic kidney defined as a categorical variable. (2012) 26, ; doi: /jhh ; published online 30 June 2011 Keywords: renal artery stenosis; revascularization; angioplasty; glomerular filtration rate Introduction Renal artery stenosis (RAS) can induce hypertension (HT) and/or aggravate it in hypertensive patients, thus making it resistant to treatment. RAS is a highly prevalent cause of secondary HT and deteriorating renal function, particularly if blockers of the renin angiotensin system are prescribed. 1 3 In most cases it is due to atherosclerosis and therefore, because of aging population, it will become even more prevalent in the future, thus representing a major cause of end-stage renal failure. Epidemiological studies have established that atherosclerotic RAS not only Correspondence: Professor GP Rossi, DMCS Internal Medicine 4, University Hospital, via Giustiniani, 2, Padova, Italy. gianpaolo.rossi@unipd.it Received 14 January 2011; revised 21 March 2011; accepted 16 May 2011; published online 30 June 2011 implies a high cardiovascular risk profile but also carries a considerable excess rate of morbidity and mortality from stroke, coronary heart disease and peripheral vascular disease. 2,3 Hence, the development of effective strategies for treatment of atherosclerotic RAS is worth an effort. Endovascular treatment by means of percutaneous renal angioplasty and stenting (PTRAS) is currently being increasingly used for ameliorating renal perfusion, lowering blood pressure (BP) and improving long-term patency in patients with RAS because angioplasty alone was found to carry a high rate of restenosis. Accordingly, PTRAS has become the treatment of choice for patients in whom either medical therapy failed to control BP, and/or with worsening of renal function. However, proof of superiority of PTRAS over medical therapy remains limited to small cohort studies and registries. 4,5

2 508 The advances in antihypertensive drug therapy and risk factor management, which can provide excellent BP control and risk reduction for many patients, prompted the undertaking of few prospective randomized trials aimed at proving superiority of PTRAS over optimized medical therapy in patients with atherosclerotic RAS. 6,7 Although these trials unexpectedly failed to show compelling benefits for revascularization, they had limitations, 8 which could affect their conclusions, as discussed below. Rationale of METRAS and limitations of previous studies We shall herein briefly recapitulate the features and limitations of the previous studies comparing endovascular treatment with medical therapy in atherosclerotic RAS to illustrate the rationale and design of METRAS. Inclusion criteria and definition of RAS: Mostof these studies, being conceived and completed before the American College of Cardiology/American Heart Association practice guidelines for renal revascularization were published in 2006, 9 could not take them into consideration Accordingly, the degree of RAS as inclusion criterion varied widely across studies, from 50% in the Scottish Study, 10 DRAS- TIC 11 and STAR 7 to the 75% degree in the EMMA Study. 12 In the latest Astral Study, patients were included only when the caring physician was uncertain that the patient would definitely have a worthwhile clinical benefit from revascularization; moreover, patients were not eligible if they required surgical revascularization or were considered to have a high likelihood of requiring revascularization within 6 months, which means that, based on a subjective definition of relevant RAS, 6 this study enrolled patients who were unlikely to benefit from revascularization and excluded those who were most likely to benefit from it. Undoubtedly, the hypothesis that PTRAS is equal or superior to medical treatment in preserving renal function should be tested only in patients who have accepted clinical indications for revascularization; 8 accordingly, the inclusion criterion in ASTRAL introduced a bias that precluded challenging or proving this hypothesis. Only 72% of the patients randomized to revascularization in the STAR Study underwent PTRAS, because the rest had hemodynamically insignificant (o50%) RAS. In ASTRAL RAS ranged between 40 and 100%, and only 60% of the patients randomized to either PTRAS or medical therapy had a RAS 470%; thus, 40% of the patients likely had hemodynamically insignificant RAS. Inclusion of patients who are unlikely to gain any benefit from revascularization also introduced a bias in favor of medical therapy. A subgroup analysis of patients with bilateral RAS 470% and with RAS 470% in a solitary kidney did not show any advantage of PTRAS over medical treatment, but this can simply reflect the choice of an inappropriate experimental endpoint, as discussed below, and/or the loss of statistical power due to the smaller sample size of the group of patients with these features. Moreover, the mean number of antihypertensive drugs per patient in the patients recruited in these trials was less than three in ASTRAL, two in the DRASTIC and p2 in the EMMA Study, 11,12 whereas the aforementioned practice guidelines recommendations suggest that PTRAS is reasonable for patients with hemodynamically significant RAS and resistant HT, defined as the failure to achieve goal BP in patients who are adhering to full doses of an appropriate three-drug regimen that includes a diuretic (Level of Evidence: B). 11 Hence, by enrolling many patients who did not meet accepted indication for revascularization, these studies are likely to bias their results in favor of medical therapy. Finally, in all these studies the RAS were quantified as arterial diameter reduction based on twodimensional images, whereas current technology based on cross-sectional images furnishes a far more accurate evaluation with use of three-dimensional reconstructions and semi-automated softwares. 14 Nephroangiosclerosis: Another yet unsolved issue is whether the presence of nephroangiosclerosis can prevent patients from benefiting from revascularization. According to a retrospective German study, 13 an intrarenal resistivity index (RI) at Doppler, which is indicative of nephroangiosclerosis, predicted no improvement in BP or renal function. This critical cutoff was claimed to allow discrimination between patients who will or will not benefit from PTRAS, as no prospective randomized study has considered the RI for the randomization to treatment thus far and this claims remains to be proven. Experimental endpoints: Most studies, including ASTRAL and the German study, assessed indexes of global renal function (as creatinine and/or creatinine clearance), and not separate estimates of glomerular filtration rate (GFR) in the ischemic and the contralateral kidney. However, as a hemodynamically significant RAS is expected to lower GFR in the ischemic kidney and to induce hyperfiltration in the contralateral kidney that is exposed to HT, it is probably naïve to expect any improvement of indexes of overall GFR after lowering BP with PTRAS. Accordingly, no clear-cut benefits of PTRAS over medical therapy could be anticipated; moreover, it remains unknown whether PTRAS can increase GFR in the ischemic kidney. Number of patients enrolled per center:instaron average one patient was stented at each center, whereas in the ASTRAL 65% of the centers enrolled only two patients per year, which suggests a selection bias, overperception of benefit, or lack of benefit, with PTRAS among physicians, and poor proficiency in delivering endovascular treatment. 6,7 Thus, the number of patients undergoing PTRAS at each center was sometimes so small as to suggest that suboptimal endovascular treatment was provided.

3 Intervention and analysis of results: DRASTIC and the study by Webster et al. 10 were aimed at comparing the BP effects of PTRA alone with medical therapy; 11 only 3.6% of the patients assigned to PTRA also received stenting. Similarly, in the EMMA Study both PTRA alone and PTRA with stenting were permitted, but only 10% of the patients underwent stenting. 12 Hence, in 90 96% of the patients in these trials medical therapy were compared with an endovascular treatment that was held to be optimal at that time but would now be considered suboptimal in a stenting era. This problem affected minimally the most recent ASTRAL because in this trial 95% received stenting. A further problem relates to high crossover rate of patients originally assigned to medical treatment to PTRAS: in DRASTIC and STAR, despite a high such rate an intentionto-treat analysis was used. In ASTRAL, the crossover rate from medical to endovascular therapy was only 6%; however, 17% of those originally randomized to endovascular treatment did not receive it. Unquestionably this introduced a further major bias, which lowered statistical power and affected the assessment of outcome. 6,7,11 Moreover, no attention was paid to the untoward effect of differences in risk control management between treatment groups. Primary endpoint: Preservation of renal function was not identified as the primary endpoint in the older studies (EMMA, Scottish Study and DRASTIC Study) The first trial having a decrease 420% of GFR as an endpoint was STAR, 7,10 12 whereas ASTRAL used as primary endpoints either estimates of overall GFR, assessed as the reciprocal of serum creatinine, or the changes in BP. 6 It also considered time to first renal event, to first major cardiovascular event and mortality as secondary endpoints. The BP change is a composite phenotype that furnishes only a piece of information on the outcome of revascularization, whereas total GFR, although routinely used in clinical practice, is affected by the limitations, mentioned above, which can lead to underestimating the benefits of PTRAS in the stenotic kidney. Use of ambulatory BP monitoring could provide a better assessment of the outcome of either treatment on BP load. Peri-procedural adverse events: The major adverse events rate in the ASTRAL Study was 9%, which is in line with the peri-procedural complication rate seen in older studies, 5 but is fourfold higher than the 2.4% observed in the ODORI Registry, 15 and the ASPIRE-2 Study 16 and the acceptable rate of complications according to leading interventional radiologists. 17 In summary, because of all these considerations we believe that clinicians are still left with uncertainties as to whether and in whom revascularization should be pursued. Only a study exploiting an optimized patient selection strategy and use of hard experimental endpoints may solve these uncertainties and thus lead to a better management of the enlarging population of patients with atherosclerotic RAS. Objectives The primary objective of the METRAS Study is to determine whether PTRAS is superior or equivalent to optimal medical treatment for preserving GFR in the ischemic kidney. Secondary objectives are to determine whether the two treatments are equivalent in: (1) lowering BP; (2) preserving overall renal function, as assessed by total estimated GFR and the reciprocal of serum creatinine, and indexes of Ca 2 þ and PO 4 3 metabolism; (3) regressing damage in the target organs of HT, including cardiac hypertrophy, microalbuminuria and aortic stiffness; (4) improving quality of life. Study design METRAS Study is a prospective multicentre randomized, un-blinded two-arm study. Materials and methods Enrollment The design of the METRAS Study is depicted in Figures 1 and 2. Hypertensive patients of both genders (age 418 years) will be eligible if they have radiological evidence of unilateral or bilateral RAS. Patients with clinical evidence suggestive of RAS will undergo angio CT to identify RAS. Clinical evidence of RAS is defined as unexplained renal dysfunction (GFR o60 ml min 1 ), uncontrolled or refractory HT 18 and/or significant worsening of renal function (defined as 20% increase of serum creatinine) after administration of a renin angiotensin system (angiotensin-converting enzyme inhibitors or angiotensin II receptor blocker) and/or an abdominal bruit, and/or evidence of atherosclerotic involvement of other sites. Eligible subjects will be offered participation to the study and must sign a written consent. Inclusion criteria Patients will be recruited if they have evidence at angio CT of RAS affecting the main renal artery or its major branches either 470% or, if o70 with post-stenotic dilatation. Fulfilment of these criteria will be assessed at a core laboratory at the coordinating center. Exclusion criteria Exclusion criteria will be (1) refusal to participate in the study, (2) previous endovascular or surgical treatment of RAS, (3) compelling indication to 509

4 510 Identification of eligible patients Unexplained renal dysfunction (GFR < 60 ml/min) or refractory hypertension or significant worsening of renal function (20% increase of S-creatinine) after ACE-I or any other clues of RV disease Informed consent Enrolment Angio-CT-evidence of significant atherosclerotic RAS No Exclude patient Yes Run-in Measurement of RI at EchoDoppler Optimization of therapy: BP < 140/90 mmhg LDL < 80 mg/dl HbA1c < 6.5% homocysteine antiplatelet therapy Goals met? Yes No Exclude patient or reconsider after 1 month 99m Tc DTPA scintiscan Final recruitment Randomization PTRAS + medical therapy medical therapy alone Figure 1 Flowchart of the study. Eligible patients will be adult hypertensive patients with clinical and radiological evidence of unilateral or bilateral RAS, as described in text. The patients will be recruited upon evidence of significant RAS affecting the main renal artery or its major branches at angio CT, defined as RAS 470% or, if o70, with post-stenotic dilatation. They will undergo an echodoppler to measure the intrarenal resistivity index (RI) to be considered for the randomization (Figure 2). During a 4- to 8-week runin period BP treatment, low-density lipoprotein-cholesterol homocysteine and diabetes will be optimized, and anti-platelet treatment will be implemented. 99m TcDTPA sequential renal scintigraphy will then be performed to measure GFR of each kidney. Finally, the patients will be randomized to either PTRAS in addition to medical therapy or optimal medical therapy alone and will enter a 5-years follow-up. Run-in Randomization Bilateral stenosis Unilateral stenosis Revascularization + medical therapy Bilateral stenosis Unilateral stenosis Medical therapy alone Time (mo) t-1 t0 t1 t2 t3 t4 t5 t6 t7 t8 t9 t10 t11 t12 Clinical evaluation x x x x x x x x x x x x x x Lab tests x x x x x x x x x x Scintiscan x x x x x x x x Renal echodoppler x x x x x x x x AngioTC x x x Echocardiography x x x x x x x ABPM x x x x x x x x x Figure 2 Overview of the study design with the scheduled visits and laboratory and imaging tests. A matching algorithm considering both intrarenal resistivity index and unilateral/bilateral stenosis will be used to randomly assign patients to treatment (revascularization or medical therapy). Such randomization criterion will allow a similar distribution of intrarenal resistivity index and an equal number of patients with uni- or bilateral stenosis in each treatment arm. PTRAS, for example, RAS 495% and/or rapidly worsening renal function, (4) fibromuscular RAS, (5) planned or on-going pregnancy, or child-bearing potential without adequate measures to prevent pregnancy, (6) life expectancy o2 years, (7) current participation to another trial possibly influencing the safety of the patient and/or the outcomes of the study, (8) comorbid conditions or any other circumstances likely to limit participation and availability to long-term follow-up studies.

5 Run-in period Eligible patients will undergo a 4- to 8-week run-in period during which BP treatment will be optimized, low-density lipoprotein-cholesterol will be lowered below 2.17 mmol l 1 (80 mg dl 1 ), homocysteine if elevated will be lowered possibly to less than 15 mmol l 1 (with folate and vitamin B6/B12 supplementation) and treatment for diabetes will be optimized to achieve, if feasible, a hemoglobin A1c o6.5%. As these patients are to be considered at high risk, antihypertensive treatment should be adjusted to attain a BP o130/85 mm Hg or to the lowest tolerated BP value. However, being aware that in these patients, because of the presence of vascular remodeling, this target BP value will be difficult to reach, 18 a target BP value of o140/90 mm Hg will be acceptable. All classes of antihypertensive drugs will be allowed paying utmost attention to the changes in serum creatinine during treatment, particularly if angiotensin-converting enzyme inhibitors and angiotensin II receptor blockers will be needed. Full doses of antihypertensive medications, including a diuretic, are expected to allow most patients to reach the target value. Statins and/or ezetimibe (in patients with history of rabdomyolysis with statins) will be titrated to achieve a low-density lipoprotein-cholesterol o2.07 mmol l 1 (80 mg dl 1 ). Treatment with oral anti-diabetic agents and/or insulin will be adjusted to reach post-prandial glycemia o11 mmol l 1. All patients will receive antiplatelet treatment with the same dose of aspirin (100 mg o.d.), or clopidogrel (75 mg o.d.) if intolerant to aspirin, or ticlopidine 19 (250 mg b.i.d), if intolerant to aspirin and clopidogrel, throughout the study period. Patients who will not attain the BP and/or the low-density lipoprotein target will be excluded from randomization. Imaging and renal function Angio CT will be performed to assess the abdominal aorta and renal artery anatomy and pathology. Utmost precautions will be adopted to minimize the chances of worsening renal function with the iodinated contrast media injection and to minimize radiation exposure. The localization of the RAS will be assessed blindly by experienced radiologists. Quantification of arterial lumen narrowing will be performed in terms of percent area reduction using a specific software (Vessel analysis, Syngo Siemens, Erlangen, Germany). Post-stenotic dilatation will be also determined and taken as a surrogate of hemodynamically relevant RAS whenever the luminal narrowing is o70% at biplane angiography. All on-site imaging measurements will be validated by a core laboratory in Padova. administration, according to guidelines ( interactive.snm.org/docs/pg_ch16_0403.pdf). If serum creatinine level after angio CT will not worsen significantly from that measured before, the patient will discontinue angiotensin-converting enzyme inhibitors and/or angiotensin II receptor blockers for 1 week and then will undergo 99TcDTPA sequential renal scintigraphy. If an increase in serum creatinine levels 420% from baseline will occur after angio CT, scintigraphy will be delayed until full restoration of renal function will be achieved. The captopril dose (50 mg per os) will be given 60 min before injection of 99mTc-DTPA (3.7 MBq per kg body weight) and a similar dose will be injected for the basal study, at least after 24 h. Blood pressure will be checked every 15 min after captopril administration. Before the scintigraphy, angiotensin-converting enzyme inhibitors/angiotensin II receptor blockers will be stopped for 3 7 days (depending on drug half-life); if withdrawal will be judged to be unsafe, the captopril scintigraphy will be omitted and only baseline 99mTc-DTPA scintigraphy will be performed. Scintigraphy data analysis and split GFR will be calculated with specific software on a nuclear medicine workstation. The captopril scintigraphy will be considered positive when a reduction of 10% or more in split renal function is observed. All scintiscan data will be evaluated and validated at the core laboratory in Padova.v Assessment of renal function Global renal function will be assessed with the MDRD formula and the reciprocal of creatinine, 20 and by urinalysis, and by measurement of serum (S)- erythropoietin, S-electrolytes, S-creatinine, S-urea, S-homocysteine, cystatin C, uric acid, PTH, PTHrelated peptide, 25OH and 1-25OH vitamin D. Assessment of target organ damage Besides the anthropometric and clinical data, total serum homocysteine, glycosylated hemoglobin, lipids (high-density lipoprotein and low-density lipoprotein-cholesterol, and triglycerides will be determined as indexes of metabolic risk. Transthoracic echocardiogram with Doppler with assessment of left ventricular mass index, relative thickness, the E/A wave peak flow velocity rate and tissue Doppler will be used to detect changes in left ventricular remodeling and diastolic filling changes Measurement of pulse wave velocity and augmentation index (Sphygmocor, West Ryde, Australia) will be used to follow the changes in aortic stiffness, as index of vascular damage. 511 Assessment of kidney perfusion 99TcDTPA renal scintigraphy will be performed on two consecutive days, before and after captopril Assessment of blood pressure Clinical and ambulatory BP monitoring will be performed to evaluate the changes of BP values in

6 512 each treatment arm and to determine the BP variability (smoothness index during day and night). 24 Assessment of quality of life Changes in quality of life after PTRAS will be assessed with the SF36 questionnaire. 25 Randomization The patients will be randomly assigned to either PTRAS, on top of optimal medical therapy (arm revascularization), or to optimal medical therapy alone (arm medical therapy) using an algorithm at the core laboratory. Because the presence of nephroangiosclerosis might affect the results and the number of the patients with bilateral stenosis will be smaller than that with unilateral stenosis, the algorithm will consider both RI and unilateral/bilateral stenosis to achieve a similar distribution of RI and an equal number of patients with uni- or bilateral stenosis in each treatment arm. Sample size Power calculation (nqueryvers, 6.0, Statistical Solutions, Saugus, MA, USA) showed that assuming a 16% dropout rate, a common s.d. of 8.0 ml min 1, an equal sample size in each treatment arm, using a two-group t-test with a 0.05 two-sided significance level, with 60 patients per arm our study will have a 99% power to detect a difference in means of GFR in the vascularized (or control untreated kidney) of 7.5 ml min 1. Treatment arms Revascularization In the patients randomized to PTRAS lesions involving the ostium and/or the main renal artery will be treated; more distal stenoses will be recorded for data analysis purposes but will not be treated. A balloon-expandable stent (Palmaz Genesis on Cordis AMIIA Delivery System, Cordis Europa, Roden, The Netherlands) will be implanted during PTRA. Patients with bilateral RAS randomized to endovascular treatment will undergo PTRAS of eligible lesions on both sides. After PTRAS the patients will continue on their antihypertensive drug regimen. The dose and number of drugs will be downtitrated, if necessary, to reach a target o130/80 mm Hg for systolic and diastolic BP values. Medical therapy The patients randomized to medical treatment will continue on the drug regimen optimized during the run-in period. Adjustment of antihypertensive drug therapy will be allowed to achieve the best possible control of BP; changes of treatment (number and doses of each drug) will be recorded for the purpose of data analysis. Crossover criteria. Patients randomized to medical therapy who will present compelling indications to PTRAS, for example, rapidly worsening renal function and/or narrowing of renal artery (RAS 490%), will be considered to have reached the categorical renal endpoint and will undergo endovascular treatment. Experimental endpoints The GFR value of assessed by 99TcDTPA in the ischemic kidney will be used as quantitative variable and compared between groups at each time point during follow-up. For the purpose of Cox regression analysis a categorical definition of kidney loss, defined as fall of GFR of the ischemic kidney to o5 ml min 1, a rapidly worsening renal function and/or narrowing of renal artery (RAS 490%), will be considered as categorical renal endpoint; rate of achievement of such endpoint will be compared between treatment arms. If suitable they will be crossed over to endovascular treatment. Secondary endpoints Secondary endpoints will be (1) lowering BP, (2) preserving overall renal function as assessed by total estimated GFR, the reciprocal of serum creatinine and indexes of Ca 2 þ 3 and PO 4 metabolism after revascularization, (3) regression of damage in the target organs of HT, including cardiac hypertrophy, microalbuminuria and aortic stiffness and (4) quality of life. Handling of potential confounders To minimize the untoward effect of differences in CV risk management, anti-platelet, lipid-lowering and anti-diabetic agents will be given to all patients if needed, and maintained at the dosage achieved at the end of the run-in period throughout the study, unless otherwise indicated. Calculation of the propensity score will allow adjusting for the possible unbalanced distribution of confounders between treatment arms. 26,27 Follow-up Visits will be scheduled at 1 (t1), 3 (t2), 6 (t3), 12 (t4) and 24 (t5) months after revascularization or beginning of the medical therapy (t0). The study will then continue in an observational setting with outpatient visits scheduled at 6-month intervals for a total of 5 years. Data collection Data will be collected using specifically designed database and forms; the building up of the database

7 will be monitored in real time at the core laboratory (see later). Statistical analysis Comparison of GFR in the ischemic kidney between groups (revascularization versus medical therapy) at each time point will be performed using Student s t-test, repeated measures analysis of variance with adjustment of potential confounders, Cox regression model for loss of kidney function as defined above. Subgroup analysis (comparison unilateral versus bilateral stenosis) will be similarly undertaken. Receiver operating characteristic curves will be used to determine if the baseline 99mTc DTPA scintiscan-derived indexes can predict the outcome of treatment using the changes in GFR over time as reference. Bland Altman plot and analysis will be used to compare the estimate of GFR obtained using cystatin C using the overall (right and left kidneys) GFR as reference. Multivariate techniques and the propensity score will be used to avoid the untoward effect of a possible unbalanced distribution of confounders between treatment arms. 26,27 Expected results With its high power this study should clarify whether PTRAS on top of optimal medical therapy is superior or equivalent to the latter alone in preventing deterioration of GFR in the ischemic kidney. Assessment of secondary endpoints will clear up some clinically relevant issues regarding BP lowering, rate of renal and major cardiovascular events and changes in quality of life after PTRAS. Duration of the study The METRAS Study will last for 5 years. This time interval is required to achieve enough renal and major cardiovascular events in this high-risk population. Ethics consideration The study ( Identifier: NCT ) has been approved by the Ethics Committee of the Azienda Università-Ospedale, Padova, Italy. The scientific committee will perform ad interim analyses of the results in the patients in both arms who have reached the end of the first and the second year. The study could be terminated prematurely if unequivocal evidence of superiority of one treatment over the other will be found. Participating centers and core laboratory This study will be performed within the Italian Society of Arterial Hypertension; this will allow enrolling and randomizing the patients needed to achieve the required power. The core laboratory in Padova will adjudicate the eligible patients based on angio CT RAS and Doppler intra-parenchymal resistance indexes, randomize patients and undertake responsibility for data collection, storage and analysis. METRAS and ongoing randomized trials Five randomized trials comparing PTRAS and medical treatment are currently ongoing (Table 1). CORAL 28 and RAVE 29 studies have recently completed enrollment, RADAR 30 and the Austrian studies ( term ¼ renal+artery+stenosis&rank ¼ 2) are recruiting patients and NITER 31 hasbeenreportedina meta-analysis, 32 butnotasafullpaperyet.allwere designed to include patients with hemodynamically significant and angiographically documented atherosclerotic RAS in hypertensive patients. However, the definition of hemodynamically significant RAS varies across these studies: 470% in NITER, 460% in the Austrian study, 450% in the RAVE study, between 60 and 80%, but with a X20 mm Hg systolic pressure gradient, or between 80 and 100% in CORAL. RADAR not only considered RAS 470% but also an intra-renal RI difference between kidneys in case of unilateral disease, and an acceleration time sec in case of bilaterally stenoses. At variance with all these studies, METRAS will enroll patients with angio CT evidence of RAS X70% or post-stenotic dilatation affecting the main renal artery or its major branches, in keeping with the accepted indication to revascularization. 2,9 Conversely, it will also avoid enrolling asymptomatic or minimally symptomatic patients with non-obstructive renal artery lesions, in whom PTRAS is not indicated because it is unlikely to give any benefits. Moreover, the ongoing studies neither considered nephroangiosclerosis in the affected kidney, as assessed with the RI value, for the randomization of the patients nor a separate randomization for patients with uni- or bilateral stenosis. At variance, the randomization scheme chosen in METRAS will ensure an equal number of patients with similar RI values and with unilateral and bilateral stenosis in each treatment arm. This should allow detection of differences, in response to PTRA between unilateral or bilateral stenosis in patients with a similar degree of nephroangiosclerosis. Although the major endpoints differ widely across studies, ranging from incidence of adverse CV and renal events, to composite endpoints entailing death, dialysis and doubling of creatinine, to the impairment of renal function estimated from overall egfr, no study was set up to assess the GFR of the ischemic 513

8 514 Table 1 Inclusion criteria and treatment arms of ongoing trials investigating PTRAS plus medical therapy versus medical therapy alone in renovascular hypertension Trial Inclusion criteria Arms Comparison of stenting versus best medical therapy for treatment of ostial renal artery stenosis: a randomized controlled trial in patients with advanced atherosclerosis ( Renal atherosclerotic revascularization evaluation (RAVE) 29 Revascularization of renal artery stenosis versus medical therapy for the treatment of ischemic nephropathy (NITER) 31 Cardiovascular outcomes in renal atherosclerotic lesions (CORAL) 28 Randomized, multi-centre, prospective study comparing best medical treatment versus best medical treatment plus renal artery stenting in patients with hemodynamically relevant atherosclerotic renal artery stenosis (RADAR) 30 PAD and unilateral ostial 460% RAS and hypertension SBP 4140 mm Hg and/or DBP 490 mm Hg, despite at least three antihypertensive drugs. SBP 4140 mm Hg and/or DBP490 mm Hg on two antihypertensive drugs with a rise in creatinine420% after ACEi or ARB; sudden onset of hypertension occurring after the age of 55 years; hypokalemia or presence of an abdominal bruit; history of flash pulmonary edema; or any three of: peripheral vascular disease, coronary artery disease, cerebrovascular disease, smoking, hyperlipidemia, diabetes or male gender. Ostial RAS X70% (determined by Duplex Doppler ultrasonography and confirmed by MR valuated by at least two experienced operators). Serum creatinine p3mgdl 1 and/or creatinine clearance (MDRD formula) X30 ml min 1, defined as stage 3 or greater CKD, based on the NKF classification. Longitudinal ultrasonographic diameter of the stenotic kidney X8 cm. BPp150/90 mm Hg with the use of less than four hypotensives drugs Documented history of hypertension on two or more antihypertensive medications or renal dysfunction, defined as stage 3 or greater chronic kidney disease (estimated GFR o60 ml min 1.73 m 2 ). One or more severe RAS by any of the following pathways: Angiographic: 460% and o100% by renal angiogram or Duplex Doppler ultrasonography: systolic velocity 4300 cm s 1 or core lab-approved MR angiogram. Hemodynamically relevant de novo unilateral or bilateral atherosclerotic RAS X70% Estimated GFR 410 ml min 1 calculated with MDRD equation, Mild, moderate or severe hypertension (defined according to the WHO guidelines) and/or renal dysfunction, Target lesion must be completely coverable by one study stent, Total target lesion length estimated to be less than 19 mm, Target lesion accessible to direct stenting, or after pre-dilation, is likely to sufficiently benefit from stenting (at the discretion of the investigator), Renal reference vessel diameter (RVD) of X4.0 mm and o7.0 mm based on visual estimation. (A): Renal artery stenting plus best medical treatment versus (B): Best medical treatment alone (A): PTRA with stenting versus (B): medical therapy alone (A): Percutaneous transluminal renal artery stenting plus the same medical therapy as in (B) versus (B): medical treatment. hypotensive drugs, statins and anti-platelets (A): Stent procedure plus optimal antihypertensive therapy. versus (B): Optimal antihypertensive therapy (A): PTRA followed by the best medical treatment for hypertension secondary to RAS according to local standards. versus (B): The best medical treatment for hypertension secondary to renal artery stenosis according to local standards Abbreviations: ACEi, angiotensin-converting enzyme inhibitors; ARB, angiotensin II receptor blockers; CKD, chronic kidney disease; DBP, diastolic blood pressure; MR, magnetic resonance; NKF, National KIdney Foundation; PTRAS, percutaneous renal angioplasty and stenting, RAS, renal artery stenosis; SBP, systolic blood pressure; WHO, World Health Organization.

9 kidney, which entails the primary endpoint defined in METRAS. This is likely that the GFR of the ischemic kidney represents the best index reflecting the outcome of either treatment. Moreover, by using a technique allowing accurate assessment of GFR, METRAS attains a high statistical power notwithstanding a relatively small sample size. Conclusions and perspectives METRAS may contribute to clarifying if PTRAS on top of optimal medical therapy is superior to the latter alone in preventing function loss in the ischemic kidney. If it will show superiority of PTRAS over medical treatment alone, the next question to be answered is if the beneficial effect of PTRAS, and the ensuing deactivation of the renin angiotensin system, can translate into an increased survival, free of cardiovascular events and a better quality of life. Assessment of these secondary endpoints in ME- TRAS will provide preliminary information on estimates of between treatment differences that could be used for planning larger studies with this regard. Finally, the measurement of GFR in ischemic and contralateral kidney could be used as reference for identifying the clinical and biochemical indexes that better allow discriminating the patients with reversible and irreversible renal damage. What is known about this topic K All trials investigating whether revascularization of renal artery stenosis (RAS) by means of percutaneous renal angioplasty and stenting (PTRAS) is advantageous over medical therapy failed to show compelling benefits for revascularization. K The measurements of the blood pressure and the glomerular filtration rate, which were used as outcomes in most trials, are notoriously composite phenotypes that may furnish partial information on the outcome of revascularization. What this study adds K The METRAS Study will clarify whether PTRAS on top of optimal medical therapy is superior or equivalent to the latter alone in preventing deterioration of GFR in the ischemic kidney as assessed as 99TcDTPA renal scintigraphy. K Assessment of secondary endpoints will clear up some clinically relevant issues including blood pressure lowering, rate of renal and major cardiovascular events, and changes in quality of life after PTRAS. Conflict of interest The authors declare no conflict of interest. Acknowledgements This study was supported by an unrestricted research grant from The FOundation for advanced Research In Hypertension and CArdiovascular diseases. References 1 Cheung CM, Hegarty J, Kalra PA. Dilemmas in the management of renal artery stenosis. Br Med Bull 2005; 73-74: Cheung CM, Wright JR, Shurrab AE, Mamtora H, Foley RN, O Donoghue DJ et al. Epidemiology of renal dysfunction and patient outcome in atherosclerotic renal artery occlusion. 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Am Heart J 2011; 161: Appendix List of participating centers and METRAS study investigators Centers Investigators 1. DMCS Internal Medicine 4, Padova, Italy Gian Paolo Rossi, Teresa M Seccia, Achille C Pessina, Massimo Puato, Matteo Vincenzi, Maurizio Cesari, Franco Bui, Piero Zucchetta, Diego Cecchin, and Paola Caielli 2. Internal Medicine, Milano, Italy Alberto Morganti 3. Endocrinology, Ancona, Italy Paolo Dessi 4. Internal Medicine, Pisa, Italy Stefano Taddei, Stefania Pinto 5. Department of Internal Medicine and Public Health, L Aquila, Italy Claudio Ferri 6. Internal Medicine, Roma, Italy Claudio Letizia 7. Internal Medicine, Bari, Italy Anna Belfiore