Percutaneous Transluminal Angioplasty (PTA) and Stenting of the Renal Arteries

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The Centers for Medicare and Medicaid Services (CMS) has decided to make no change in the NCD addressing PTA of the renal arteries (Pub. 100-3, 20.7, B1). CMS has also decided to add clarifying language to 20.7, D in order to decidedly explain that coverage of PTA with stenting not specifically addressed or discussed in this NCD is at local Medicare contractor discretion.

Decision Memo: To: Administrative File: CAG 00085R4 From: Steve Phurrough, MD, MPA Director, Coverage and Analysis Group Marcel Salive, MD, MPH Director, Division of Medical and Surgical Services Sarah McClain, MHS Lead Analyst Lawrence Schott, MD, MS Lead Medical Officer Subject: Coverage Decision Memorandum for Percutaneous Transluminal Angioplasty (PTA) and Stenting of the Renal Arteries Date: February 14, 2008 I. Decision The Centers for Medicare and Medicaid Services (CMS) has decided to make no change in the NCD addressing PTA of the renal arteries (Pub. 100-3, 20.7, B1). CMS has also decided to add clarifying language to 20.7, D in order to decidedly explain that coverage of PTA with stenting not specifically addressed or discussed in this NCD is at local Medicare contractor discretion. II. Background In approximately 90% of cases, renal artery stenosis (RAS) – unilateral or bilateral narrowing of the lumen of the renal arteries – is the result of generalized atherosclerosis, which progressively diminishes blood flow to the kidneys and may elevate blood pressure (BP) or impair functioning of the kidneys. Such atherosclerotic vascular narrowing, however, is a systemic disease that affects not only the kidneys but also the arteries supplying the heart, brain and other vital organs. Patients with RAS and generalized atherosclerosis more often die from cardiovascular causes such as a heart attack or stroke, rather than from kidney failure. Overall, atherosclerotic RAS ranges in prevalence from about 30% in patients with coronary artery disease to about 50% in patients who are elderly or have diffuse atherosclerotic disease. The severity or percent RAS that is reported widely varies in clinical significance and is generally poorly correlated with a patient’s kidney function. Measurement, for example, of the degree of narrowing and flow through the stenotic renal segment is imprecise and non-standardized, and there is no reliable diagnostic test or baseline characteristic that accurately predicts a patient’s post-treatment kidney function outcome. Importantly, while RAS may occur in combination with hypertension and kidney disease, a stenotic renal vessel, in which plaque has partially blocked blood flow, may also be an incidental finding, may not be the cause of a patient’s disease state, or may lie proximal to a chronically diseased kidney which is already beyond recovery. It is thus uncertain which patients will improve, remain unchanged, worsen or be harmed following treatment. Based upon each patient’s presenting history, the treatment options for atherosclerotic RAS presently include aggressive medical therapy administered alone or in combination with endovascular therapy and/or open surgical reconstruction of one or both renal arteries. Triple medical therapy with antihypertensive, antihyperlipidemic and antiplatelet drugs consisting of multiple antihypertensive agents prescribed to lower blood pressure, statins to lower low density lipoprotein (LDL) cholesterol and stabilize plaques, and antiplatelet agents to reduce thrombosis (clotting of the arteries). While the current NCD addresses angioplasty, at present, nearly all endovascular renal artery procedures utilize angioplasty with stent placement across the narrowed vessel. Surgical renal artery reconstruction is typically reserved for concomitant pararenal abdominal aortic reconstructions for aortic aneurysms or severe aortoiliac occlusive disease, complicated renal artery anatomy or aneurysms, and/or repair of endovascular interventions that have resulted in chronic restenosis or are acutely complicated by dissection, thrombosis, perforation or bleeding. Angioplasty with and without stenting and surgical reconstruction all fall within the term “renal artery revascularization (RAR).” Endovascular and surgical interventions incur procedural risks with potential for morbidity and mortality. The most common major complication of percutaneous procedures is acute renal failure. Other complications include contrast-induced nephropathy, dissection, thrombosis, segmental infarction, perforation, bleeding, and renal and systemic atheroembolization, especially in patients with concomitant advanced aortoiliac disease. Surgery additionally incurs all the risks of a major abdominal procedure. Considering the general uncertainty regarding evaluation and management of patients with atherosclerotic RAS, as well as controversy about the balance of risks and benefits for alternative medical, surgical and endovascular treatments, CMS opened this national coverage analysis to evaluate Medicare coverage policy for renal artery revascularization procedures. III. History of Medicare Coverage History of Medicare Coverage for Percutaneous Transluminal Angioplasty As described in paragraph 3 of section B1 of the Medicare National Coverage Determination (NCD) Manual for PTA (20.7) , since at least 1994 percutaneous transluminal renal angioplasty (PTRA) has been nationally covered to treat atherosclerotic obstructive lesions: “Of the renal arteries for patients in whom there is an inadequate response to a thorough medical management of symptoms and for whom surgery is the likely alternative. The PTA for this group of patients is an alternative to surgery, not simply an addition to medical management.” 1 Benefit Category Determination For an item or service to be covered by the Medicare program, it must meet one of the statutorily defined benefit categories outlined in the Social Security Act. Surgical renal artery reconstruction and percutaneous transluminal renal angioplasty with or without stenting fall under the benefit categories set forth in section §1861(b)(3) (inpatient hospital services), a part A benefit under §1812(a)(1), and §1861(s)(1) (physician services), a part B benefit. This may not be an exhaustive list of all applicable Medicare benefit categories for this item or service. IV. Timeline of Recent Activities Date Action February 26, 2007 CMS internally generated national coverage analysis (NCA) and initiated reconsideration of current coverage policy for PTA of the renal arteries. July 18, 2007 MedCAC considered PTA and stenting of the renal arteries. November 20, 2007 Proposed decision memorandum posted; 30-day comment period begins. February 14, 2008 Final decision memorandum posted; NCD becomes effective. V. FDA Status Renal stents are class III devices 2 , 3 which require premarket approval (PMA) and for which documentation, including engineering and clinical data, must be submitted demonstrating that the data and information in the application constitute valid scientific evidence and provide reasonable assurance that the device is safe and effective for its intended use. 4 , 5 The FDA (2002) has approved two Premarket Approval (PMA) applications for renal stents (P890017/S010 and P020007), each subject to conditions of approval and indicated for use only in patents with atherosclerotic disease of the renal arteries following suboptimal or failed PTRA of de novo or restenotic lesions. 6 , 7 Neither of these PMAs for stenting following suboptimal or failed PTRA was reviewed by the FDA’s Circulatory System Devices Panel. These stenting devices are no longer being marketed, and there are presently no FDA approved devices for primary stenting or distal embolic protection in the renal arteries. The FDA’s Manufacturer and User Facility Device Experience (MAUDE) database for medical device adverse event reporting suggested (2006) that “virtually all of the renal stenting procedures currently conducted in the U.S. are performed using stents not indicated for use in the renal vasculature, most commonly including biliary stents. As explained by Dr. Cavanaugh in his 2006 article “Biliary stents are Class II devices under the FDA's risk-based classification system and are marketed under the premarket notification (510[k]) pathway. Biliary stents are not indicated for use in any part of the vasculature (unless a separate PMA has been approved for such use) and are typically indicated only for palliative treatment of malignant neoplasms in the biliary trees of patients with terminal cancer. As a result of the risk/benefit profile for these patients, marketing clearance under 510(k) requires minimal evaluation of long-term performance characteristics such as stent durability. Clinical data are only provided in unusual cases and, for a biliary stent, would be unrelated to renal artery stenosis.” 8 In 2003 the FDA issued a 510(k) clearance letter (K033394 (PDF, 153KB)) for the PALMAZ GENESIS transhepatic biliary stent (Cordis), indicated for use only in palliation of malignant neoplasms in the biliary tree, with the following limitation: “The Office of Device Evaluation has determined that there is a reasonable likelihood that this device will be used for an intended use not identified in the proposed labeling and that such use could cause harm. Therefore, in accordance with Section 513(i)(1)(E) of the Act [Federal Food, Drug and Cosmetic Act], the following limitation must appear in the Warnings section of the device’s labeling: The safety and effectiveness of this device for use in the vascular system have not been established.” [According to the published study design, all patients in the stent therapy arm of the ongoing “Cardiovascular Outcomes in Renal Atherosclerotic Lesions” (CORAL) trial will undergo implantation of a Cordis Genesis stent. 9 ] On May 4, 2004, a Class I recall was initiated for the PRECISE RX Nitinol Stent transhepatic biliary stenting system (Cordis) with the following “Reason for Recall” on the FDA’s website: “Some physicians use this device for vascular use. This use has not been cleared by the FDA. When used this way, air may be introduced into the patient via the stent system causing serious problems including coma, seizure and stroke. There have been nine patient injuries due to air embolism and seven incidents of malfunction in connection with the use of this system outside of its approved indications. Cordis is recalling its revised instructions for use and strongly recommends that physicians limit the use of the PRECISE RX Stent to FDA-approved uses only.” 10 VI. General Methodological Principles When making national coverage decisions, CMS evaluates relevant clinical evidence to determine whether or not the evidence is of sufficient quality to support a finding that an item or service falling within a benefit category is reasonable and necessary for the diagnosis or treatment of illness or injury or to improve the functioning of a malformed body member. The critical appraisal of the evidence enables us to determine to what degree we are confident that: 1) the specific assessment questions can be answered conclusively; and 2) the intervention will improve health outcomes for patients. An improved health outcome is one of several considerations in determining whether an item or service is reasonable and necessary. A detailed account of the methodological principles of study design that the agency utilizes to assess the relevant literature on a therapeutic or diagnostic item or service for specific conditions can be found in Appendix A . In general, features or clinical studies that improve quality and decrease bias include the selection of a clinically relevant cohort, the consistent use of a single good reference standard, and the blinding of readers of the index test, and reference test results. Public comments sometimes cite the published clinical evidence and give CMS useful information. Public comments that give information on unpublished evidence such as the results of individual practitioners or patients are less rigorous and therefore less useful for making a coverage determination. CMS uses the initial public comments to inform its proposed decision. CMS responds in detail to the public comments on a proposed decision when issuing the final decision memorandum. VII. Evidence A. Introduction This summary represents the body of evidence evaluating renal artery revascularization for the treatment of patients with atherosclerotic RAS. The discussion of evidence reviewed focuses upon whether the body of evidence is adequate to draw conclusions about the health benefits of these interventions compared to aggressive medical therapy alone, as well as whether the body of evidence is generalizable to and demonstrates improved health outcomes for Medicare patients. In this decision memorandum, the key health outcomes of most interest to CMS are kidney function, cardiovascular event rates, mortality and quality of life. Of lesser weight and value to CMS are post-procedural patency rates reflecting frequency of restenosis (recurrent narrowing greater than an arbitrary 50% threshold of a treated vessel after intervention), as well as surrogate endpoints such as patients’ blood pressure (BP). “Control of BP is actually a very soft endpoint most often measured by a combination of the decrease in BP and an alteration in the number of drugs used to control the high BP. This means of evaluation is insufficient because physicians will often exchange three or four less-effective drugs for one or two more powerful or appropriate drugs, and suddenly the BP will be more effectively controlled, but simultaneously a renal artery stent had been used, or the change in drugs might occur after the stent had been placed. The result is that it would appear as if the stent were responsible for the improved BP control, when in fact the change might be due in part or in toto to the altered drug regimen.” 11 B. Discussion of evidence reviewed 1. Literature Search In addition to AHRQ’s extensive search for relevant research designs (excluding abstracts) in the MEDLINE database from inception to April 23, 2007, CMS searched PubMed (1990 to present) for all RCTs evaluating medical, endovascular or surgical treatments with RAS. Studies must have presented original data for adult humans and been published in peer-reviewed English language journals. Six randomized controlled trials were identified. Three 12 , 13 , 14 of those RCTs were evaluated in the 2003 Cochrane review, and two 15 , 16 of those three were evaluated in AHRQ’s 2006 and updated 2007 comparative effectiveness reviews. 2. External technology assessments and clinical reviews Cochrane (2003) Selection criteria for the 2003 Cochrane Collaboration systematic review included randomized and quasi-randomized controlled trials that compared angioplasty with medical therapy in hypertensive patients with renal artery stenosis of > 50% reduction in luminal diameter and at least six months follow-up. Three trials involving a total of 210 patients met the review’s inclusion criteria but only 4 patients in those trials were stented - none in Webster (1998), 2 patients in Plouin (1998), and 2 patients in van Jaarsveld (2000). The Cochrane review found available data insufficient to conclude that balloon angioplasty without stenting was superior to medical therapy in lowering BP of atherosclerotic RAS patients in whom BP could be pharmacologically controlled. In patients with hypertension refractory to medical therapy, there was weak evidence that angioplasty lowered BP more effectively than medical therapy. There were no differences between treatments in renal function. 17 AHRQ (2006 and 2007) AHRQ’s original 2006 Comparative Effectiveness Review (CER) noted there was no published evidence directly comparing angioplasty with stenting versus aggressive medical treatment with currently available drugs for atherosclerotic RAS. 18 AHRQ’s search strategy was extensive and comprehensive. In its 2006 search, AHRQ identified 2163 citations in the scientific literature. Members of its Technical Expert Panel and other domain experts contributed 28 additional articles for consideration. An updated 2007 search yielded 185 new citations, nine of which met AHRQ’s eligibility criteria for inclusion. 19 As in the original CER, none of the additional nine publications evaluated relative effects of intensive medical therapy and angioplasty with stent for atherosclerotic RAS. AHRQ reiterated in 2007 that overall study quality remained limited by inadequate reporting and/or data collection, incomplete analyses and inconsistent use of interventions such as combining angioplasty with and without stent, limited or difficult assessment of applicability due to restrictive patient eligibility or inadequate reporting, inconsistent outcome metrics, and limited statistical power due to small sample size. AHRQ’s 2007 update described the following findings: Almost two-thirds of studies were of poor methodological quality and more than half were of limited applicability to the population of interest. No RCTs compared angioplasty with stent and aggressive medical treatment with ACE inhibitors, statins, and anti-platelet drugs (Tier I studies 20 ). The two most relevant RCTs (Tier II studies: Webster 1998 and Plouin 1998) did not compare interventions that are currently used for patients with RAS. Only 2 patients in Plouin’s (1998) RCT received stents and ACE inhibitors were rarely employed. Other comparative studies (Tier III) were methodologically flawed or did not compare angioplasty and medical treatment. There were a substantial number of cohort studies (Tier IV) that prospectively evaluated angioplasty with stent, but very few cohort studies of medications - none of which explicitly evaluated aggressive medical treatment with ACE inhibitors, statins, and anti-platelet drugs. Thus, indirect comparisons across the cohort studies were limited. Among the comparative studies there was some evidence of a relative benefit in BP after angioplasty, particularly in patients with bilateral disease; however, this conclusion was based largely on the end-of-study (not primary endpoint after which some treatment cross-over occurred) of one RCT (Webster 1998) and either clinically though not statistically significant differences, partially statistically significant differences, or nonrandomized trial data. Among the comparative studies there was no difference in kidney function outcomes. Studies generally included too few patients and were of too short a duration to make definitive assessments regarding differences in clinical event outcomes of interest: mortality, cardiovascular event rates, and quality of life. Although studies were generally too small to detect any but large differences in mortality rates, no differences in mortality were found between interventions, up to about 5 years. Very high mortality rates, over 40 percent within 6 years, occurred mostly in studies of patients with either high-grade stenosis (> 75%) or bilateral disease. Direct and indirect comparisons of interventions generally found no clinical or statistically significant differences in kidney outcomes. However, only in some of the angioplasty with stent placement studies did patients have improved kidney function. That implied that, at least in a (poorly described) subset of patients with atherosclerotic RAS, kidney function was more likely to improve after angioplasty with stent placement than with continued medical treatment. Both trials and most of the other comparative studies found some evidence of greater BP improvement after angioplasty than with medical treatment; although the benefit of angioplasty may be limited to patients with bilateral disease. In contrast, cohort studies of angioplasty generally found somewhat lower reductions in BP (6-32/0-17 mm Hg) than cohorts of medical interventions (20-50/8-42 mm Hg), though it was not possible to draw conclusions about the relative effect on BP measurements of different interventions. Comparative studies found similar rates of cardiovascular disease regardless of intervention, though these studies were not designed to find significant differences in cardiovascular events. The data from cohort studies on cardiovascular events were too sparse to draw conclusions. A single trial (Krijnen 2005) found no consistent difference in quality of life between angioplasty and medical therapy. Adverse events, variably defined, occurred in up to 13% of patients receiving angioplasty, though serious long-term adverse events were rare. Reported adverse events from antihypertensives were relatively minor and transient. A variety of indicators of the severity of atherosclerotic RAS and of health problems, such as poorer kidney function, severity of stenosis, and coexisting cardiovascular disease predicted poorer outcomes in patients with atherosclerotic RAS. The reviewed studies did not report any indicators that may predict improved outcomes. Two trials found that patients with bilateral RAS had better outcomes after angioplasty than medical therapy, compared to patients with unilateral disease. In comparative studies, captopril test, renogram, recent hypertension, and stenosis greater than 80% were not predictors of either worse outcome overall or of which intervention would result in better outcomes. Among patients receiving angioplasty, there was little consistent evidence about which diagnostic tests would predict more favorable outcomes. Two studies found that Doppler ultrasonography findings were predictive of outcomes after angioplasty, but they disagreed as to whether resistive index predicted worse or better outcomes. No study that met eligibility criteria reported analyses of whether periprocedural interventions, such as different drugs or different approaches, affected either complications or long-term outcomes. AHRQ (2007) also made these conclusions about the evidence: “The evidence does not support one treatment approach over the other for the general population of people with ARAS. Weak evidence suggests no difference in mortality rates. There is acceptable evidence that, overall, there is no difference in kidney outcomes between patients treated medically only and those receiving angioplasty without stent, although the relevance of this finding to current practice is questionable due to changes in treatment options. However, improvements in kidney function were reported only among patients receiving angioplasty. There is acceptable evidence that combination antihypertensive treatment results in large decreases in blood pressure, but there is inconsistent evidence regarding the relative effect of angioplasty and medication on blood pressure control. There is weak evidence suggesting similar rates of cardiovascular events between interventions; however, it is likely that the studies were too small to detect different rates of cardiovascular events. Weak evidence suggests no difference in QoL with medical treatment alone or with angioplasty. The evidence does not adequately assess comparisons of adverse events between medical treatment alone and angioplasty. There is weak evidence that patients with bilateral RAS may have more favorable outcomes with angioplasty than medical therapy. Weak or inconsistent evidence does not support statements on whether other clinical features (such as demographics or indicators of RAS severity) or diagnostic tests predict whether patients would have better clinical outcomes with angioplasty or with medical therapy alone. There is no evidence regarding the value of periprocedural interventions with angioplasty.” 3. Internal technology assessment Cochrane and AHRQ have reviewed the breadth of evidence for treatment of atherosclerotic RAS. We will not repeat that review here. However, CMS identified a total of 6 RCTs that evaluated surgical, medical and/or endovascular treatments for atherosclerotic RAS. The results are tabulated below and subsequently described. Table 1. Published Randomized Controlled Trials (RCTs) RCT Patient Demographics Pts Stented Endpoints Comments Weibull (1993) N = 58 (all unilateral RAS) N = 29 PTRA N = 29 Surg.RAR 0 Surgical group better primary patency rate, not secondary patency rate NS in primary or secondary results for BP response or renal function following all additional therapy after restenoses Relatively young, nondiabetic pts randomized betw April1984 and February 1990 5/29 pts (17% ) in PTRA group, and 9/29 pts (31%) in surgical group had major complication but the frequency of major and minor complications did not significantly differ betw groups in this small trial Webster (1998) “SNRASCG” N = 135 total pts (multicenter) 80 pts nonrand 55 pts rand N = 25 PTRA N = 30 med. tx (28 bilateral and 27 unilateral RAS) 0 NS in unspecified office BP (at 6 month 1 o endpoint) No pts stented Did not allow ACE inhibitors Dates of trial recruitment and randomization were unstated Plouin (1998) “EMMA” N = 59 (all unilateral RAS) N = 23 PTRA(S) N = 29 medical tx 2 NS in mean ambulatory BP (at 6 month 1 o endpoint) Only 2 pts stented Used enalapril in only some pts Trial recruitment between Jan 1992 and June 1995 van de Ven (1999) N = 84 N = 42 PTRA(S) N = 42 PTRAS (12) 42 PTRAS had better vascular patency than PTRA NS clinically Intention to treat showed no change in clinical results at 6 months for PTRA or PTRAS Trial recruitment between Dec 1993 and March 1997 van Jaarsveld (2000) “DRASTIC” N = 106 total pts (77-78% unilat RAS) N = 56 PTRA(S) N = 50 medical tx 2 NS at 12 month mean office SBP or DBP, daily drug doses or renal function 54 pts angioplasty alone; 2 pts stented 22 patients crossed over after 3 months and had received angioplasty Studied betw Jan 1993 and Nov 1998 Uzzo (2002) N = 52 N = 25 Surg.RAR N = 27 medical tx 0 NS identified between surg. and medical outcomes Pts randomized to surgical RAR and medical mgmt over unspecified 8 year period (NS = No statistically significant difference) Weibull, et al. (1993) Weibull and colleagues’ trial (Sweden) compared renal angioplasty without stenting (PTRA) versus surgical reconstruction as initial therapy for unilateral RAS and measured technical results (primary and secondary patency) as well as effects on BP and renal function. Patency was defined as < 50% RAS not requiring reintervention. Patients with ≥ 50% restenosis underwent repeated interventions with PTRA or surgery. Primary results were for therapeutic effect achieved after the first performed intervention, and secondary results were for effect achieved following addition of all therapeutic efforts after restenoses, including 4 PTRA patients who required surgery and 1 surgical patient who underwent PTRA. All patients’ cases were discussed by a surgeon, interventional radiologist and endocrinologist; and following consensus that both PTRA and surgery were possible on the basis of morphologic appearance, a patient was randomly assigned to a treatment group. Fifty-eight non-diabetic patients ≤ 70 years of age with severe hypertension (untreated BP ≥ 160 mm Hg), serum creatinine < 300 mmol/L and significant unilateral atherosclerotic RAS (main RAS diameter ≤ 2 mm and renal vein renin ratio of stenotic to nonstenotic side ≥ 1.5) within 1 cm from the aorta were randomized to PTRA (N = 29, median age 60, range 41–69 years) or to surgery (N = 29, median age 54, range 38-70 years). BP, renal function and angiography (to document renal artery patency) were obtained at 10 days, 1 year and 2 years after PTRA or surgery. Treatment was “technically successful” (defined as total elimination of the stenosis) in 24 of 29 (83%) of PTRA patients and in 97% of surgical patients (28 reconstructions were patent and 1 occluded), which did not represent a significant difference between groups. In technically successful cases, the primary patency rate after 2 years was 75% (18 of 24 patients) for de facto treated arteries in the PTRA group (62% for “intention to treat”) and 96% in the surgical group (27 of the 28 successful revascularizations were patent), which represented a statistically significant difference (p = .05). At the end of follow-up after all redo procedures, the secondary renal artery patency rate was 90% in the PTRA group and 97% in the surgical group, which was not a statistically significant difference. Primary and secondary results for both BP and renal function showed no significant differences between the PTRA and surgical groups. Acknowledging that the series consisted of highly selected, relatively young non-diabetics with renovascular hypertension and unilateral RAS admitted to the referral center, Weibull, et al. (1993) thought “from a technical point of view, the results should be the same with unilateral or bilateral lesions” and concluded that PTRA should be the first choice of therapy for atherosclerotic RAS causing renovascular hypertension “if combined with intensive follow-up and aggressive reintervention” with PTRA or surgical reconstruction. 21 Webster, et al. (1998) Webster and colleagues’ Scottish and Newcastle Renal Artery Stenosis Collaborative Group (SNRASCG) multicenter trial compared the effects on BP and renal function after renal angioplasty without stenting (PTRA) versus medical therapy in hypertensive patients with both unilateral (N = 27) and bilateral (N = 28) stenoses in the randomized groups. A total of 135 eligible patients were identified, and the majority were not randomized. Only 55 of SNRASCG patients (mean age 61, range 40-75 years) with resistant hypertension (sustained hypertension diastolic BP ≥ 95 mm Hg on at least two anti-hypertensive drugs) and ≥ 50% RAS defined by angiography were randomized to either PTRA (N = 25, including 12 bilateral and 13 unilateral stenoses) or medical therapy (N = 30, including 16 bilateral and 14 unilateral stenoses). All patients were observed during an initial 4-week run-in period on a fixed drug regimen and subsequent changes were measured from the 4-week baseline. Results showed a “consistent, clinically important fall in BP in all groups between referral and end of the run-in phase.” In 12 patients with bilateral RAS randomized to angioplasty, no significant change in systolic or diastolic BP was noted at the study’s 6 month primary endpoint compared to 16 patients treated medically. A statistically significant (P < 0.05) decrease in office systolic BP was reported at the “latest follow-up” that widely ranged from 3-54 months. In unilateral RAS patients, no statistically significant or clinically important differences in outcome were observed between groups; and “if anything, the systolic BP fell more in the medical than in the intervention group.” In the study’s 80 nonrandomized patients, “no important differences were observed between the intervention patients and the medical patients, either at 6 months or most recent follow-up.” There were also no significant differences or trends in serum creatinine observed between or within the angioplasty and medical groups during follow-up. The SNRASCG study found no statistically significant difference in BP change between the angioplasty and medical groups at the study’s 6 month primary endpoint for either bilateral RAS or unilateral RAS randomized patients. Following PTRA, no patient’s hypertension was cured (defined as achieving normal BP off all drug therapy); there was no demonstrable benefit in terms of renal function or event-free survival; and “complications of the procedure were an important source of morbidity, even in the hands of experienced radiologists in specialist centers.” The SNRASCG (1998) investigators additionally discussed that: “Unfortunately there has been a lack of standardization of the methods of BP measurement, and critically, a failure to take into account regression to the mean from the time of referral. Our data demonstrate very clearly the substantial fall in BP that can be observed simply by a short period of structured follow-up with no intervention or change of therapy, even in patients who may have been in regular attendance at hypertension clinics. This run-in period to establish a baseline is an essential part of any study to evaluate changes in BP and is just as important in a trial of intervention as it would be in a trial of a new anti-hypertensive drug.” 22 Plouin, et al. (1998) Plouin and colleagues’ EMMA (French) multicenter trial was designed to evaluate the efficacy and safety of angioplasty for lowering BP in patients less than 75 years old (N = 49, mean age 59) with unilateral atherosclerotic RAS. After a 2-6 week run-in period on a standardized stepwise antihypertensive regimen, patients were hospitalized and randomized during qualifying angiography (all patients underwent angiography and had their renal arteries classified into five grades: no stenosis, < 60%, 60-75%, > 75%, thrombosis) to continued antihypertensive drug therapy (N = 26) or to angioplasty (N = 23, including 2 with stenting). In the medical treatment group, 13 patients had a grade 60-74% RAS and 13 patients had “high-grade” ≥ 75% RAS. In the angioplasty group, 15 patients had a grade 60-74% RAS and 8 patients had “high-grade” ≥ 75% RAS. In patients randomized to angioplasty, antihypertensive drug therapy was stopped post-procedure but was resumed if hypertension persisted. The study’s primary endpoint was 24 hour ambulatory blood pressure (ABP) determined at termination. Termination took place 6 months following randomization or earlier in patients who developed refractory hypertension defined as diastolic BP > 104 mm Hg. The study’s secondary endpoints were treatment score (defined as number of antihypertensive agents administered) and incidence of complications. Two medical patients and 6 of 23 (26%) angioplasty patients suffered angiographic or procedural complications including 1 dissection with segmental renal infarction and 3 restenoses in the angioplasty group, which the authors found to be “substantial and higher than in many retrospective series.” Early termination was required for refractory hypertension in 7 patients in the medical group, and the antihypertensive treatment was resumed in 17 patients in the angioplasty group. Mean ABP at study termination, the study’s primary outcome measure, did not significantly differ between the medical therapy and angioplasty groups. The EMMA (1998) investigators concluded that angioplasty is a drug-sparing procedure that involves some morbidity in patients with unilateral atherosclerotic RAS, but that “previous uncontrolled and unblinded assessments of angioplasty overestimated its potential for lowering BP.” The authors also concluded that “most patients undergoing angioplasty still needed antihypertensive agents 6 or 12 months after the procedure” and that “reduction in treatment required by patients undergoing angioplasty should therefore be weighed against the risks of complications and restenosis.” 23 van de Ven, et al. (1999) van de Ven and colleagues’ single center trial (Netherlands) compared PTRA (N = 42, mean age 64.8 years) with PTRAS (N = 42, mean age 65.6) in hypertensive patients (BP > 160/95 with or without medication) who had ostial atherosclerotic RAS within 1 cm of the aortic lumen. Block randomization was utilized to balance intake in each treatment arm. About 20% of patients had prior PTRA and both treatment groups had a similar distribution of unilateral and bilateral RAS. Secondary PTRAS was allowed if PTRA failed either immediately (≥ 50% restenosis by elastic recoil) or during 6 month follow-up. Primary success rate (< 50% restenosis) following PTRA was 57% (24 of 42 patients) compared to 88% (37 of 42 patients) after PTRAS. At 6 months renal angiography was repeated, and the primary patency rate was 29% for PTRA and 75% for PTRAS. Restenosis after a successful primary procedure occurred in 48% of PTRA patients and 14% of PTRAS patients. Twelve PTRA patients underwent secondary stenting for primary or late failure of PTRA within the 6 month follow-up period, and primary PTRAS versus primary PTRA plus PTRAS as rescue therapy had similar outcomes. Evaluation based on intention-to-treat analysis showed no statistically significant difference in clinical results at 6 months for PTRA or PTRAS. Procedural complications (nearly identical for both groups) included bleeding (19%), femoral artery aneurysm (5%) and renal artery dissection/occlusion/thrombosis (5%), as well as cholesterol embolism in 4 of 42 patients (10%) in each treatment group. Renal failure induced by cholesterol embolism, defined as at least 20% increase in plasma creatinine concentration maintained for 1 month or longer, occurred in 3 of the 4 patients with embolism in the PTRAS group and in 2 of the 4 patients with embolism in the PTRA group. van de Ven, et al. (1999) thought that PTRAS was a better technique than PTRA to achieve vascular patency in ostial atherosclerotic RAS and, considering the burden of reintervention after PTRA, that “primary PTRAS is a better approach to use.” However, the authors discussed that while PTRAS may give patients a better start, long term follow-up would be needed to assess whether renal stenting is beneficial in terms of renoprotection; and the investigators concluded: “Whether patients with ostial atherosclerosis renal artery stenosis should be treated at all is unclear. Ischemic nephropathy is a multifactorial disease, involving stenosis related ischemia and factors such as dyslipidemia, nephrosclerosis, cholesterol embolism, and in areas of advanced renal perfusion, the effect of hypertension. In cases of advanced renal dysfunction, whether restoration of renal perfusion is sufficient to avert deterioration in the long term is also unclear. Complications of PTRAS in these patients, many of whom have widespread atherosclerosis disease, are severe and include a substantial incidence of procedure-related dialysis dependency and death... We believe that a prospective comparative study of PTRAS and medical treatment will show which groups of patients should receive PTRAS.” 24 van Jaarsveld, et al. (2000) van Jaarsveld and colleagues’ large Dutch Renal Artery Stenosis Intervention Cooperative (DRASTIC) trial screened 1205 patients at 26 centers and randomly assigned 106 hypertensive patients (mean age 60, range 18-75 years) with normal or mildly impaired renal function (serum creatinine ≤ 2.3 mg per dl) and unilateral or bilateral atherosclerotic RAS (≥ 50%) to PTRA (N = 56) or medical therapy (N = 50). The trial evaluated particularly unilateral stenosis, including 43 of 56 patients (77%) in the angioplasty group and 39 of 50 patients (78%) in the medical therapy group with unilateral RAS. Patients were included who had diastolic BP ≥ 95 mm Hg despite treatment with 2 antihypertensive drugs or an increase of ≥ 0.2 mg per dl in serum creatinine during therapy with an ACE inhibitor. There was no run-in period. Mean office systolic and diastolic BP (primary outcome measures), doses of antihypertensive drugs and renal function were assessed at 3 and 12 months. Renal artery patency was assessed at 12 months. At the end of the randomized portion of the DRASTIC trial at 3 months, results showed no significant change between groups in mean systolic or diastolic BP. Due to persistent hypertension despite treatment with ≥ 3 drugs or because of deterioration in renal function, 22 patients in the medical group underwent angioplasty (44% crossover) after 3 months; but according to intention-to-treat analysis, there were no significant differences between groups at 12 months for either systolic or diastolic BP, daily drug doses or renal function. While the study’s crossover limitations were discussed, the DRASTIC (2000) investigators nonetheless concluded that angioplasty had “little advantage over antihypertensive-drug therapy” for the treatment of hypertensive patients with RAS. Discussing the concept of hemodynamically significant stenosis, the authors also noted no correlation between BP response and baseline severity of RAS. 25 Uzzo, et al. (2002) Uzzo and colleagues’ trial (USA) compared differences in event-free survival between RAS patients managed medically (N = 27) and surgically (N = 25) over 8 years at the Cleveland Clinic (median follow-up was 74 months overall and 85 months for survivors). Surgical management consisted of revascularization by a single surgeon and included aortorenal bypass (6), splenorenal bypass (3), hepatorenal bypass (8), ileorenal bypass (6), endarterectomy (1) plus aortic replacement with renal artery reimplantation (1). Prior to randomization, patients required angiographic confirmation of bilateral RAS involving > 75% of the luminal diameter, high-grade (> 75%) disease involving a solitary kidney, or unilateral high grade (> 75%) stenosis with azotemia defined as serum creatinine > 1.5 mg/dL and glomerular filtration rate (GFR) < 70 mL per minute. Exclusion criteria were baseline serum creatinine > 4.0 mg/dL, BP poorly controlled (DBP > 100 mm Hg) despite adequate medical management or comorbid conditions that prohibited ability to tolerate surgical revascularization. Follow-up was quarterly for the first 2 years, then every 6 to 12 months thereafter. Once a patient reached a stop point event, follow-up was yearly until the time of death. Repeat angiography was performed for 20% increase in serum creatinine over baseline, 20% decrease in GFR from baseline, > 1 cm decrease in kidney size, or evidence of functional deterioration on renal nuclear scan. The trial’s primary endpoint was a comparison of stop point events between medical and surgical groups, defined as: (1) the development of poorly controlled hypertension (DBP > 100 mm Hg) despite adequate medical management, (2) “creatinine failure” as defined by reduction in GFR ≥ 50% from baseline, rise in serum creatinine > 4 mg/dL (5 mg/dL if baseline serum creatinine was between 2 and 4 mg/dL), doubling of serum creatinine from baseline, or development of end-stage renal disease requiring dialysis, (3) the development of an intercurrent “atherosclerotic” event such as a myocardial infarction or cerebrovascular accident, or (4) death. A total of 67% of patients (35/52) reached an endpoint, including 67% (18/27) in the medical group and 68% (17/25) in the surgical group. There were no statistically significant differences in baseline demographics between the two groups, and results showed no statistically significant differences in the endpoints reached between groups. There were no statistically significant differences in death-free survival, dialysis-free survival or BP control. Cox proportional hazard survival analyses of interacting baseline demographic factors with likelihood of reaching an endpoint failed to identify statistically significant differences between groups at the 95% confidence interval, and analysis of variance comparing changes in GFR over time between groups likewise yielded no statistically significant differences. Uzzo, et al. (2002) acknowledged that the power of their study was limited by its small sample size (N = 52), that the power to detect even a large group difference such as a twofold change in median survival was only 53%, and that this “underscores the importance of large-scale prospective cooperative studies on the subject.” 26 4. MedCAC On July 18, 2007, the Medicare Evidence Development & Coverage Advisory Committee (MedCAC) met to discuss the body of evidence, hear presentations and public comment, and make recommendations to CMS regarding currently available endovascular and surgical co-interventions for the treatment of patients with atherosclerotic RAS. The results of a technology assessment performed by the Tufts New England Medical Center Evidence-Based Practice Center were presented by Dr. Balk, and the panel heard presentations from Dr. Cooper, Dr. Dworkin, Dr. Sos and Dr. Linas. Ten speakers, including professional society representatives and a manufacturers’ representative, addressed the MedCAC panel. At the request of the committee chair following the public comment portion of the meeting, Dr. Cavanaugh of the FDA addressed the current status of FDA approval for devices used to stent renal arteries. The panel conducted subsequent extensive discussion, as well as a question and answer period with the presenters and speakers; and the panel formally voted on following questions. MedCAC Voting Questions On a scale from 1 to 5, where 1 = not confident, 3 = uncertain and 5 = highly confident , the MedCAC panel voted upon three multiple part questions. The overall average score is tabulated below following each subpart of the questions. For the treatment of patients with atherosclerotic RAS, how confident are you that the evidence is adequate to draw conclusions about safety and clinical effectiveness of the following renal artery interventions: a) Surgical renal artery reconstruction (RAR)? 2.92 b) PTRA without stent placement? 2.92 c) PTRAS with bare metal stents? 2.85 d) PTRAS with drug-eluting stents? 1.00 Based on the evidence presented, how confident are you that the published results apply to: a) Medicare patients with typical comorbidities? 3.69 b) Providers (facilities/physicians) in community practice? 2.15 c) Patient subgroups not represented in the study populations? 1.69 Based on the evidence presented for patients with atherosclerotic RAS, how confident are you that compared to aggressive medical treatment alone there are improved key health outcomes attributable to the following co-interventions: a) Surgical renal artery reconstruction (RAR)? 2.31 b) PTRA without stent placement? 2.08 c) PTRAS with bare metal stents? 3.15 d) PTRAS with drug-eluting stents? NA (evidence not adequate) Where 1 = strongly agree, 2 = agree, 3 = uncertain, 4 = disagree and 5 = highly disagree , the MedCAC panel voted upon and a mean score recorded for the following final question. Based on the evidence presented, should Medicare national coverage of any non-medical treatments for atherosclerotic RAS be limited only to patients enrolled in qualified clinical research studies? 2.23 After the voting, additional discussion focused upon discussion questions about the strengths, weaknesses and practical issues regarding randomized trials. A scoresheet containing votes of all panelists, as well as a roster, agenda and transcript of the July 18, 2007 MedCAC meeting , are electronically available. 27 5. Guidelines According to the opening paragraph of section “3.5 Treatment of Renovascular Disease: Renal Artery Stenosis” of the American College of Cardiology/American Heart Association (ACC/AHA) 2005 Practice Guidelines: “Treatment of renal arterial disease should serve to aid in the normalization of blood pressure and to preserve renal function, and possibly to reduce risk of cardiovascular events and mortality. Both medical (pharmacological) and revascularization strategies should be considered for patients with documented renal arterial disease. The relative efficacy and safety of medical and endovascular strategies remains an area of active clinical investigation.” 28 The guidelines make specific recommendations for medical treatment of RAS, as well as indications for revascularization, catheter-based intervention and surgery. Medical Treatment Angiotensin-converting enzyme inhibitors are effective medications for treatment of hypertension associated with unilateral RAS. (Class I, Level of Evidence: A) 29 Angiotensin receptor blockers are effective medications for treatment of hypertension associated with unilateral RAS. ( Class I, Level of Evidence: B ) Calcium-channel blockers are effective medications for treatment of hypertension associated with unilateral RAS. (Class I, Level of Evidence: A ) Beta-blockers are effective medications for treatment of hypertension associated with RAS. ( Class I, Level of Evidence: A) Revascularization Percutaneous revascularization may be considered for treatment of an asymptomatic bilateral or solitary viable kidney with a hemodynamically significant RAS. ( Class IIb, Level of Evidence: C ) The usefulness of percutaneous revascularization of an asymptomatic unilateral hemodynamically significant RAS in a viable kidney is not well established and is presently clinically unproven. ( Class IIb, Level of Evidence: C ) The Guidelines noted that “recommendations regarding the role of percutaneous revascularization of asymptomatic renal disease are made largely on the basis of expert opinion and are not based on evidence that treatment of asymptomatic RAS improves any renal or systemic outcome, including renal preservation, blood pressure, or cardiovascular morbidity or mortality:” Hypertension Percutaneous revascularization is reasonable for patients with hemodynamically significant RAS and accelerated hypertension, resistant hypertension, malignant hypertension, hypertension with an unexplained unilateral small kidney, and hypertension with intolerance to medication. ( Class IIa, Level of Evidence: B ) Preservation of Renal Function Percutaneous revascularization is reasonable for patients with RAS and progressive chronic kidney disease with bilateral RAS or a RAS to a solitary functioning kidney. ( Class IIa, Level of Evidence: B ) Percutaneous revascularization may be considered for patients with RAS and chronic renal insufficiency with unilateral RAS. ( Class IIb, Level of Evidence: C ) Congestive Heart Failure and Unstable Angina Percutaneous revascularization is indicated for patients with hemodynamically significant RAS and recurrent, unexplained congestive heart failure or sudden, unexplained pulmonary edema (see text). ( Class I, Level of Evidence: B ) Percutaneous revascularization is reasonable for patients with hemodynamically significant RAS and unstable angina (see text). ( Class IIa, Level of Evidence: B ) Surgery for RAS Vascular surgical reconstruction is indicated for patients with atherosclerotic RAS and clinical indications for intervention, especially those with multiple small renal arteries or early primary branching of the main renal artery. ( Class I, Level of Evidence: B ) Vascular surgical reconstruction is indicated for patients