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

Dear Dr. Phurrough,

Medtronic, the world’s leading medical technology company specializing in implantable and interventional therapies that alleviate pain, restore health and extend life, supports CMS’s proposed decision to make no change in the current coverage policy addressing PTA of the renal arteries (Pub. 100-3, 20.7, B1).

CMS’s proposed decision provides Medicare beneficiaries equal access to therapy options that are available to the general community of “patients in whom there is an inadequate response to a thorough medical management of symptoms and for whom surgery is the likely alternative”¹. While we support the enrollment in randomized clinical trials such as CORAL, we believe limiting coverage only to patients enrolled in clinical studies would deny Medicare beneficiaries access to a safe and effective therapy option - renal artery angioplasty and stenting. We agree that absent any additional data to demonstrate serious patient harm due to renal artery revascularization or evidence to support medical management over renal artery angioplasty and stenting², no changes in coverage should occur.

The proposed decision memo provides a detail review of the available evidence in section VII. Evidence /B. Discussion of evidence reviewed. However, subsection 6. Professional Society Position Statements could be improved by summarizing the positions represented by other professional societies such as the Society of Vascular Surgery (SVS), Society of Interventional Radiology (SIR), Society of Cardiovascular Angiography and Interventions (SCAI) and the American College of Cardiology (ACC). Currently, the only professional society position statement represented is from the American Society of Nephrology (ASN).

Thank you for the opportunity to comment on your decision to uphold the current coverage status for renal artery angioplasty and stenting. We believe your decision will result in additional peer-reviewed publications and clinical trials to support evidence-based treatment strategies. Please contact us if we can be of any assistance.

References:
1. NCD for Percutaneous Transluminal Angioplasty (PTA) Pub. # 100-3, Manual Section # 20.7, version # 5, effective date 4/30/2007, implementation date 7/30/2007

2. Balk, Ethan, Raman, Gowri; Comparative Effectiveness of Management Strategies for Renal Artery Stenosis: 2007 Update; AHRQ Comparative Effectiveness Review Number 5 Update

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December 20, 2007

Lawrence Schott, MD, MS
Coverage and Analysis Group
Centers for Medicare and Medicaid Services
Department of Health and Human Services
7500 Security Blvd.
Baltimore, MD 21244

RE: Proposed Decision Memo for Percutaneous Transluminal Angioplasty (PTA) and Stenting of Renal Arteries (CAG-00085R4)

Dear Dr. Schott:

On behalf of the 2,300 members of the Society for Vascular Surgery (SVS), we offer the following comments on the Centers for Medicare & Medicaid Services’ (“CMS”) Proposed Decision Memorandum for fourth reconsideration of the National Determination of Coverage for Percutaneous Transluminal Angioplasty (PTA), particularly regarding the stenting of renal arteries.

SVS appreciates the thorough and complete process that CMS has undertaken with regard to this reconsideration of its coverage indications for renal PTA and stenting, including convening a meeting of the MedCAC in which SVS was pleased to participate. SVS fully appreciates the conundrum that coverage for renal angioplasty and stenting represents. This treatment clearly does benefit many patients, yet there is a dearth of Level 1 evidence supporting it use. In our March 28, 2007 comment letter to CMS on this subject, we recommended that the Agency retain its current coverage policy until such time as more data is published. We greatly appreciate CMS’ agreeing with our request, and SVS fully supports CMS’ proposed decision to make no change in coverage for PTA and stenting of renal arteries at this time.

As the specialty that has been treating atherosclerotic renovascular disease for over 40 years, and evaluating the outcomes thereof, the SVS is in the unique position to confidently share with CMS those therapies that work and have good outcomes for patients. Indeed it is worth emphasis that the literature on open surgical revascularization is the evidence body supporting the benefit of renal revascularization. We recognize that clinical decision making in renovascular disease is often complex, and “benefit” from revascularization is often evident only by examination of long term outcomes. This is particularly true as indications for renal revascularization have progressively shifted from control of hypertension alone to long term preservation of renal function. Thus, the lack of level 1 data does not, in SVS’s opinion, imply that percutaneous renal balloon angioplasty and stenting lacks efficacy.

Surgical revascularization was the standard of care for renovascular disease over many decades. Yet the standard for initial treatment in many patient subsets has changed as percutaneous endovascular therapy clearly carries a lower mortality and morbidity risk profile. The surgical literature demonstrated excellent durability of open surgical revascularization in stabilizing or improving renal function, but with significant cost in terms of perioperative morbidity and mortality. Thus the advent of a percutaneous intervention, wherein the patient enjoys the benefits of revascularization with fewer risks and complications compared to open surgical procedures, has been embraced by vascular surgeons as an option for treating renal artery stenosis. Indeed, as renal stent frequencies have risen, the number of open surgical renal bypass operations has fallen dramatically. While the absolute number of open surgical renal revascularizations never approached the current frequency of percutaneous renal intervention, the percentage reduction in Medicare claims for the three CPT codes used to report open renal revascularization are the following: CPT 35536 down 79% from 1996 to 2005; CPT 35560 down 79% from its peak in 1995 to 2005, and CPT 35631 down 36% from its peak in 1996 to 2005. Thus, while open surgical renal revascularization is still performed and still remains an important treatment option for renal preservation, these data serve to document a paradigm shift in first line therapy from an open approach to percutaneous intervention.

SVS believes that there are distinct patient and anatomic subsets wherein the benefit of percutaneous renal stenting is clear based on available evidence, and CMS’ decision to retain its current coverage policy guarantees access to care for Medicare patients with these presenting conditions. Given that between 8-15% of patients who develop end stage renal disease (ESRD) have only atherosclerotic renal artery stenosis (ARAS) as the documented pathology, treatment of this disease state is compelling.

The evidence is clear that atherosclerotic renal artery stenosis is a progressive disease which threatens renal function. In the Caps study, which was a prospective natural history study undertaken at the University of Washington, 170 patients with renal artery stenosis greater than 60 percent were followed for a mean of 33 months. Hemodynamic progression of disease was seen in 31 percent of the 295 arteries studied. Nine of the 295, or three percent, progressed to complete occlusion. However, the incidence of renal atrophy at two years was much more substantial; 21 percent of the kidneys with greater than 60 percent stenosis demonstrated renal atrophy. Natural history studies, such as the one mentioned above, have shown that ARAS tends to progress over time. Kidneys with stenotic renal arteries are at risk for atrophy and deterioration in renal function. Therefore, adequate control of blood pressure cannot be considered a clinical victory in patients with ARAS. In many cases addressing the renal artery stenosis can positively impact renal function. Marone and Cambria identified revascularization as clinically beneficial in those patients with rapid decline in excretory renal function, and/or revascularization to a single functioning kidney. Indeed, in its most dramatic form, revascularization has been shown in selected circumstances to retrieve patients from renal replacement therapy! The benefits to both the patient and the health care system are obvious.

However, SVS wishes to stress that percutaneous renal stenting should be limited at this time to patients with poorly controlled hypertension or ischemic nephropathy in the presence of a severe proximal renal artery stenosis (e.g. a stenosis sufficient to cause a blood pressure gradient across the lesion). SVS believes there is insufficient evidence to support prophylactic stenting; treatment of “clinically silent” or “drive-by” renovascular lesions.

SVS appreciates the opportunity to submit these comments. Please feel free to contact Pam Phillips, Director of Health Policy and Government Relations at 703-573-7894 or PPhillips@vascularsociety.org, if we can provide further information.

Yours truly,

K.Wayne Johnston, MD
President
Society for Vascular Surgery

Robert M. Zwolak, M.D.
Chair, Health Policy Committee
Society for Vascular Surgery

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Steve Phurrough, MD, MPA,
Director Coverage and Analysis Group,
Centers for Medicare and Medicaid Services,
7500 Security Boulevard,
Baltimore, MD, 21244

Title of NCA: Percutaneous Transluminal Angioplasty (PTA) and Stenting of the Renal Arteries (CAG-00085R4)

Dear Dr. Phurrough:

Cordis welcomes the opportunity to comment on this important subject.

Cordis strongly supports the draft recommendation to retain existing coverage for this important treatment option.

Raising the question of limiting coverage for a procedure that has become the standard of care raises important questions regarding physician and patient access to optimal treatment choices. Your recommendation retains the ability of the physician to identify and choose the optimal form of treatment for an individual patient, which is both commendable and vital.

We do, however, note that in your draft decision memorandum you state concerns regarding the depth of available data for renal artery stenting. Over many years renal artery stenting has been shown to be a safe and effective procedure. This has been demonstrated by extensive clinical data [1-14], FDA approvals for renal stent indications based on demonstrated efficacy and safety [15] and the decisions by physicians on a patient-by-patient basis which have cumulatively lead to this procedure becoming the standard of care for revascularization [16].

It should also be noted that available data from clinical trials on the non-interventional option, medical therapy, raise questions related to “real world” outcomes.

Medical therapy, while well defined in randomized controlled trials (RCT’s), can be any of a varied combination of medications in the clinical setting [17]. Patient compliance, while extremely high in RCTs, has been shown to be as low as 33% in the real-world clinical setting of chronic multi-drug administration [18]. This suggests that the benefits in clinical outcomes seen in RCTs may be greatly diminished in real world use. In this context, medical devices effectively remove poor patient compliance as an issue. Therefore, while it is certainly reasonable to identify medical therapy as a comparator, the resultant data from well-controlled trials with high rates of patient compliance are not necessarily representative of the real world benefit. However, we do believe that, like renal artery stenting, the use of medical therapy, in the form seen as optimal in the eyes of the treating physician, is an important treatment option for patients who present with atherosclerotic renal artery disease.

We would, therefore, suggest that renal revascularization outcomes are at least as well understood as those for medical therapy. When combined with the fact that renal stenting is the standard of care for those requiring revascularization, these points strongly support your recommendation to retain the physicians option to use percutaneous transluminal renal artery stenting (PTRAS) as they see fit.

Cordis shares your desire to generate an ever-growing body of quality clinical evidencefor any therapy, including renal artery stenting. This has been demonstrated by our current support of the CORAL study as well as several previous trials. However we also acknowledge the practical challenges in generating some of these data, as highlighted in your draft decision memorandum.

While we fully support the CORAL study, we do not think it would be appropriate to limit coverage solely to patients enrolled in this study for several reasons:

As with most studies, there are considerable patient exclusion criteria and there are a limited number of sites. In addition, randomization results in the likelihood of patients referred for an intervention receiving medical therapy instead. These combined factors would result in many patients being denied access to treatment that their physicians deem necessary and would create an inequity in the patient population presenting with this disease.

Furthermore, we wish to comment on the recommendations of the renal MedCAC, as cited in the draft decision memorandum. As reported in the written conclusions of the MedCAC, the MedCAC appeared to vote in favor of limiting coverage to patients enrolled in qualified clinical studies. The specific question was “Based on the evidence presented, should Medicare national coverage of any non-medical treatments for astherosclerotic RAS be limited only to patients enrolled in qualified clinical research studies?” The voting members averaged 2.36 on a 5-point scale with 5 reflecting “strongly disagree” and 1 meaning “strongly agree.”

However, in viewing this apparent conclusion, it is most important to understand that there was considerable discussion and expression of concern from the MedCAC voting panel. As stated by one panel member, “…how clear will it be to the people who read this (the vote) that we’re voting for a group as a whole, but that many of us feel that there are subgroups in which these therapies may be beneficial and it needs to be viewed from that perspective?” In response, the Chairman stated that, “you should absolutely make comments to that effect in explaining your vote and it will be a misuse of the results of our proceedings today if people ignore the comments – those are absolutely critical.” [19] We feel that it is important to be aware of this information as the MedCAC recommendation was mentioned in the draft decision memorandum without this important additional commentary.

So, while there is a broad desire to see a growing body of clinical data for PTRAS and for that matter medical therapy, we firmly believe in the ability of the medical community to self-regulate in their application of either of these treatment options. The effectiveness of this approach has been well demonstrated by the decrease in the use of renal revascularization as a treatment option since 2005.

Source: MedPAR Database, Inpatient: DRG 315 - Principal Procedure code = 39.50 (Angioplasty) or 39.90 (Stent), Outpatient: Claims with both non-coronary stent placement (CPT 37205 or 37206) and percutaneous angioplasty or atherectomy of renal or visceral artery (35471, 35490) - Principal Dx 440.1- Renal Artery Atherosclerosis.

These data are suggestive of physicians optimizing their patient selection criteria for a given treatment choice and supports the position that physicians are best placed to make decisions as to the optimal treatment option for a given patient. The joint AHA / ACC treatment guidelines [20] are an additional demonstration of the clinical community taking the lead in providing strong treatment guidelines for physicians to consider when treating an individual patient.

Therefore, in closing, we once again firmly state our agreement with the CMS recommendation to retain the existing coverage for PTRAS. We believe that this position is in the interests of patients as it maintains the ability of the physician to select the most appropriate form of treatment for each individual patient.

If you have any questions about this submission, please contact Dr. Liesl Cooper (908) 412-3000.

Sincerely,

Liesl M. Cooper, PhD
Vice President, Health Economics & Reimbursement
Cordis Corporation

Cc: Marcel Salive, MD, MPH - Division Director, Division of Medical and Surgical Supplies
Kathleen Buto, Vice President, Health Policy
Brian G. Firth, MD, PhD, FACC - VP Medical Affairs and Health Economics Worldwide p>References:

1) Rees, CR, Palmaz, JC, Becker, GJ, et al. Palmaz stent in atherosclerotic renal arteries: Preliminary report of a multicenter study. Radiology 1991; 181:507.
2) van de Ven, PJ, Beutler, JJ, Kaatee, R, et al. Transluminal vascular stent for ostial atherosclerotic renal artery stenosis. Lancet 1995; 346:672.
3) Blum, U, Krumme, B, Flugel, P, et al. Treatment of ostial renal-artery stenoses with vascular endoprosthesis after unsuccessful balloon angioplasty. N Engl J Med 1997; 336:459.
4) Tuttle, KR, Chouinard, RF, Webber, JT, et al. Treatment of atherosclerotic ostial renal artery stenosis with the intravascular stent. Am J Kidney Dis 1998; 32:611.
5) Zeller, T, Frank, U, Muller, C, Burgelin, K. Predictors of improved renal function after percutaneous stent-supported angioplasty of severe atherosclerotic ostial renal artery stenosis. Circulation 2003; 108:2244.
6) Rocha-Singh, K, Jaff, MR, Rosenfield, K. Evaluation of the safety and effectiveness of renal artery stenting after unsuccessful balloon angioplasty: The ASPIRE-2 Study. J Am Coll Cardiol 2005; 46:776.
7) van de Ven, PJ, Kaatee, R, Beutler, JJ, et al. Arterial stenting and balloon angioplasty in ostial atherosclerotic renovascular disease: A randomised trial. Lancet 1999; 353:282.
8) Burket, MW, Cooper, CJ, Kennedy, DJ, et al. Renal artery angioplasty and stent placement: Predictors of a favorable outcome. Am Heart J 2000; 139:64.
9) Watson, PS, Hadjipetrou, P, Cox, SV, Piemonte, TC. Effect of renal artery stenting on renal function and size in patients with atherosclerotic renovascular disease. Circulation 2000; 102:1671.
10) van de Ven, PJ, Beutler, JJ, Kaatee, R, et al. Transluminal vascular stent for ostial atherosclerotic renal artery stenosis. Lancet 1995; 346:672.
11) Burket, MW, Cooper, CJ, Kennedy, DJ, et al. Renal artery angioplasty and stent placement: Predictors of a favorable outcome. Am Heart J 2000; 139:64.
12) Leertouwer, TC, Gussenhoven, EJ, Bosch, JL, et al. Stent placement for renal arterial stenosis: where do we stand? A meta-analysis. Radiology 2000; 216:78.
13) Burket, MW, Cooper, CJ, Kennedy, DJ, et al. Renal artery angioplasty and stent placement: Predictors of a favorable outcome. Am Heart J 2000; 139:64.
14) Harden, PN, MacLeod, MJ, Rodger, RS, et al. Effect of renal-artery stenting on progression of renovascular failure. Lancet 1997; 349:1133.
15) FDA PMA approvals for the CORDIS PALMAZ® Renal Stent (P8900171/SO10) and the Medtronic AVE Bridge ® Renal Stent (P020007)
16) AHRQ Comparative Effectiveness of Management Strategies for Renal Artery Stenosis 2007 update to the Final Research Review published 19th November 2007
17) Differences between clinical trial efficacy and real-world effectiveness. Am J Manag Care. 2006 Nov;12(15 Suppl):S405-11
18) Catalan VS, LeLorier J. Predictors of long-term persistence of statins in a subsidized clinical population. Value Health. 2000;3:417-426
19) Centers for Medicare and Medicaid Services, Medicare Evidence Development and Coverage Advisory Committee. July 18th 2007. Page 0214 http://www.cms.hhs.gov/faca/downloads/id39c.pdf
20) Hirsch A, Haskal Z, Hertzer N, et al. ACC/AHA 2005 practice guidelines for the management of patients with peripheral arterial disease (lower extremity, renal, mesenteric, and abdominal aorta). Circulation 2006;113:e463-e654

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December 20, 2007

Steve Phurrough, MD, MPA
Director, Coverage and Analysis Group
Centers for Medicare and Medicaid Services
Department of Health and Human Services
7500 Security Boulevard, Mail Stop C1-09-06
Baltimore, MD 21244

Re: Proposed Decision Memo for Percutaneous Transluminal Angioplasty (PTA) and Stenting of the Renal Arteries (CAG-00085R4)

Dear Dr. Phurrough:

Boston Scientific Corporation’s Peripheral Interventions Division appreciates the opportunity to present these comments and policy recommendations on the Centers for Medicare and Medicaid Services’ (CMS) proposed decision memo (CAG-00085R4) for percutaneous transluminal angioplasty (PTA) and stenting of the renal arteries.

Boston Scientific is a worldwide developer, manufacturer and marketer of medical devices. For more than 25 years, Boston Scientific has advanced the practice of less-invasive medicine by providing a broad and deep portfolio of innovative products, technologies and services across a wide range of medical specialties.

Boston Scientific is conducting the Renaissance Trial, a prospective, multi-center trial designed to study the safety and effectiveness of the Express® SD Renal Stent in the treatment of renal artery disease. Boston Scientific has submitted results from the Renaissance Trial to the FDA and is currently seeking FDA approval of its Express SD Renal Stent.*

Executive Summary
Boston Scientific applauds CMS’ proposal to maintain the status quo for Medicare coverage for renal artery PTA and stenting for patients who have renal artery stenosis (RAS). We agree with CMS that, in the absence of reported serious patient harms, it would be inappropriate to restrict Medicare beneficiaries’ access to a therapy that is standard of care as reflected in the American College of Cardiology (ACC) and the American Heart Association (AHA) guidelines. Importantly, these guidelines are also endorsed by the National Heart, Lung and Blood Institute (NHLBI).

Boston Scientific therefore urges CMS to finalize the Proposed Decision Memo and maintain current coverage for renal PTA and stenting.

CMS Should Maintain Current Coverage for Renal PTA and Stenting
Boston Scientific recommends maintaining the status quo for renal PTA and stenting based on the following information:

• Renal PTA and stenting is, and has long been, selectively provided to patients based on specialty society and NHLBI-endorsed treatment guidelines and criteria specified in the PTA National Coverage Determination (NCD) and by local Medicare contractors in their local coverage determinations (LCDs).
• Despite CMS’ statement that, “true consensus regarding a best treatment strategy does not exist among all specialists caring for [RAS] patients,” a review of the public positions of a variety of medical specialty societies indicates strong support for maintaining patient access to renal PTA and stenting.
• A review of Medicare claims data for renal stenting indicates that, after an initial increase in procedure volume after its introduction, renal stent volumes have flattened and even declined slightly in recent years, suggesting thoughtful patient selection rather than uncontrolled use.
• A change in Medicare coverage for renal PTA and stenting will not address issues with patient enrollment in the CORAL Trial.
• Data from Boston Scientific’s Renaissance Study for the Express® SD Stent demonstrate that this stent successfully treats ostial RAS.

ACC/AHA Guidelines Recommend Renal PTA and Stenting for Selected Patients
Although some commentors at the July 2007 MedCAC meeting expressed concern regarding the lack of a defined patient population that benefits from renal PTA and stenting, ACC/AHA guidelines clearly identify appropriate patient groups for percutaneous revascularization. In its 2005 guidelines for managing peripheral arterial disease (PAD), the ACC and AHA recommend renal artery revascularization and stenting for patients with hemodynamically significant ostial atherosclerotic RAS associated with the following conditions:

• Accelerated hypertension
• Resistant hypertension
• Malignant hypertension
• Hypertension with a unilaterally small kidney
• Hypertension with intolerance to medication
• Renal insufficiency
• Recurrent congestive heart failure or “flash” pulmonary edema,
• Refractory heart failure
• Refractory angina pectoris

The guidelines also state that balloon angioplasty with bailout stent placement if necessary is recommended for fibromuscular dysplasia (FMD) lesions. All of these recommendations are based on a review of available literature and grounded in Level B Evidence.

In its comments on CMS’ announcement to review coverage for renal PTA and stenting, the AHA reiterates its support for revascularization in the following patient groups:

In addition to being endorsed by the NHLBI, these guidelines have been published in two respected peer-reviewed journals and are widely adopted across specialties including interventional cardiology, cardiology, vascular surgery, and interventional radiology.

Moreover, in a review of LCDs in the Medicare Coverage Database, Boston Scientific found five LCDs covering 17 states. Although there are slight variations across policies, in general these LCDs recommend patient selection criteria similar to those described in the ACC/AHA guidelines:

• Patients must be eligible for PTA of the renal artery AND:
• Patients must have ostial lesions; or
• Patients must have had a suboptimal result after PTA; or
• Patients must have a dissection.

The following table details which states have LCDs addressing renal stenting (Table to be provided in email copy):

Strong Support for Renal PTA and Stenting Among Specialty Societies, Professional Groups
The CMS proposal to make no change to the NCD for PTA or to LCDs regarding renal stenting largely reflects the recommendations of numerous professional specialty societies that are notably consistent in their support for renal PTA and stenting. Specifically, in their comments to CMS regarding the coverage consideration, the following specialty groups indicated their support for maintaining current coverage until additional data are available:

December 20, 2007

Steve Phurrough, MD, MPA
Director, Coverage and Analysis Group

RE: Comment on Proposed Decision Memo for Percutaneous Transluminal Angioplasty (PTA) and Stenting of the Renal Arteries (CAG-00085R4)

On behalf of the Society for Cardiovascular Angiography and Intervention, we would like to congratulate the Centers for Medicare and Medicaid Services on their insightful proposed decision on coverage for percutaneous transluminal angioplasty and stenting of the renal arteries dated November 23, 2007. This is what we recommended to CMS in our attached comments to the Medicare Coverage Advisory Committee meeting on this issue in July.

The Society for Cardiovascular Angiography and Interventions (SCAI) is a professional association representing over 4,000 invasive and interventional cardiologists. SCAI promotes excellence in cardiac catheterization, angiography, and interventional cardiology through physician education and representation, and quality initiatives to enhance patient care.

The review of the pertinent literature is well written and comprehensive. As the leading professional organization representing physicians with intimate understanding of the management of atherosclerosis, and with the ideal skills for percutaneous therapy for renal artery stenosis, the SCAI appreciates the comments regarding meaningful clinical trials data and outcomes.

As an organization, the SCAI has always been dedicated to optimal care of our patients with atherosclerosis, and many of our members and officers have published some of the peer- reviewed literature cited in your comments. We agree that meaningful clinical trial endpoints that include cardiovascular event rates, renal function, mortality, and quality of life should be determined. As physician experts and patient advocates, we have always been interested in trials which investigate outcomes beyond patency of a treated artery.

The outcomes of renal artery stenting have improved, largely due to miniaturization of devices, better patient selection, and improved technical skills of operators. Safety of this procedure has not been brought into question. However, clinical advantage and outcomes of this procedure is the issue at hand. As we mentioned in our letter dated March 28, 2007, the recommendations of the American College of Cardiology/American Heart Association guidelines for the management of peripheral arterial disease clearly state that renal artery stent deployment is a class I and II recommendation for the common clinical syndromes affecting patients with renal artery stenosis.

We do not believe that the revised and updated Agency for Healthcare Research and Quality document (AHRQ Document No. 07(08)-EHC004-U-EF, November 2007) adds anything more to the data well summarized in your decision document.

It is curious, however, that you chose to include detailed guidelines for informed consent of Medicare beneficiaries. We believe that providers have an obligation to have comprehensive discussions with their patients about the risks, benefits and alternatives for any therapy, including lifestyle modification, pharmacotherapy, and intervention. There is nothing specific regarding renal artery stent deployment that would alter this. Your outlined list would be relevant for any Medicare beneficiary regardless of therapy however, it is not specific to renal stent placement and should be removed from this decision memorandum.

We look forward to working with other professional medical organizations and regulatory agencies to develop and populate important clinical trials to advance our knowledge of optimal therapy for our patients with renal artery stenosis.

I also wish to express my appreciation to SCAI Members Christopher White, M.D. FSCAI and Michael R. Jaff, D.O. who were the primary authors of this document.

Sincerely,

/s/

Bonnie H. Weiner, MD, FSCAI
President
Society for Cardiovascular Angiography and Interventions

cc: Marcel Salive, MD, MPH
Director, Division of Medical and Surgical Services

Sarah McClain, MHS
Lead Analyst

Lawrence Schott, MD, MS
Lead Medical Officer

ATTACHMENT

VIA ELECTRONIC TRANSMISSION

June 18, 2007

Steve Phurrough, M.D., M.P.A.
Director, Coverage and Analysis Group
Centers for Medicare and Medicaid Services

RE: Written Comments for the Meeting of the Medicare Coverage Advisory Committee—July 18, 2007 (Percutaneous Transluminal Angioplasty (PTA) and Stenting of the Renal Arteries - CAG- 00085R4)

Dear Dr. Phurrough:

The Society for Cardiovascular Angiography and Interventions (SCAI) is a professional association representing over 3,700 invasive and interventional cardiologists. SCAI promotes excellence in cardiac catheterization, angiography, and interventional cardiology through physician education and representation, and quality initiatives to enhance patient care.

The Society for Vascular Medicine and Biology (SVMB) is a professional organization that was founded in 1989 to foster a broad mission. The goals of the Society are to improve the integration of vascular biological advances into medical practice, and to maintain high standards of clinical vascular medicine. We are responding to the questions that the Centers for Medicare and Medicaid Services’ (CMS) has developed for the Medicare Coverage Advisory Committee (MedCAC) meeting on July 18, 2007. This is part of CMS’s reconsideration of coverage for renal stenosis.

Discussion Question 1: Considering the common incidental nature of atherosclerotic RAS, discuss the:

• Degree of correlation between %RAS and kidney function

Response: Incidental (asymptomatic) renal artery stenosis found at coronary or peripheral angiography is much more common than previously suspected.^1,2 Screening angiography found renal artery stenosis (> 50% diameter stenosis) in 18% of 196 consecutive patients undergoing cardiac catheterization for suspected coronary artery disease. In patients with coronary artery disease the incidence of incidental, unsuspected renal artery stenosis climbed to 22% (33/152). A large study examined the incidence of renal artery stenosis diagnosed by screening angiography during cardiac catheterization and found incidental renal artery stenosis in 30% of 1,235 consecutive angiograms.³ Significant renal artery stenosis (> 50% diameter stenosis) was found in 15% of patients, and was noted to be bilateral in one-third of cases. Multivariate predictors of renal artery disease included age, associated coronary artery disease, congestive heart failure, female gender, and peripheral arterial disease. Hypertension was not an associated variable. A third trial in 177 consecutive patients undergoing cardiac catheterization for suspected coronary artery disease found renal artery stenosis in 25% of the patients, with hemodynamically significant lesions in 11%. Multivariate analysis demonstrated that the strongest predictor of renal artery stenosis was the extent of coronary artery disease.⁴ The presence of incidental renal artery stenosis has been significantly associated with mortality.^5,6 Conlon and coworkers performed screening abdominal aortography on 3,987 patients undergoing cardiac catheterization. No complications related to the screening abdominal aortogram occurred. Significant (≥ 50% diameter stenosis) renal artery stenosis was found in 362 (9.1%) patients, and severe (≥ 75% diameter stenosis) renal artery stenosis was found in 191 (4.8%) patients. Approximately one-fifth (n =33) of patients with severe renal artery stenosis had bilateral involvement. The finding of renal artery stenosis at the time of coronary or peripheral angiography has a profoundly negative effect on survival. Conlon and coworkers found that the four-year survival of patients with asymptomatic, severe (≥ 75% diameter stenosis) renal artery stenosis incidentally discovered during cardiac catheterization was 57% compared to 89% in patients without severe renal artery stenosis. The presence of severe renal artery stenosis was independently associated with mortality. In a multivariate model, the negative impact of incidental renal artery stenosis on survival persisted despite successful revascularization of coronary artery disease. As the severity of renal artery stenosis increased from 50% to 75%, 75% to 95%, and > 95%, the four-year survival decreased to 70%, 68%, and 48% respectively. Patients with bilateral severe (≥ 75% diameter stenosis) renal artery stenosis had the lowest four-year survival rate (47%) compared to 59% for those with unilateral disease. Progression or worsening of renal artery stenosis occurs regardless of medical therapy, and renal artery occlusion generally causes permanent loss of renal excretory function. Over a seven year period, 24,312 patients underwent cardiac catheterization, and 14,152 (58%) had abdominal aortography to screen patients for asymptomatic renal artery stenosis.³ The development of new lesions or progression of known stenoses was assessed in a cohort of 1,189 patients who underwent two abdominal aortograms separated by a mean of 2.6 ± 1.6 years. A new renal artery stenosis or renal artery stenosis progression was seen in 11.1% of the patients. Progression from normal to > 75% stenosis in one or more arteries was associated with a decline in renal function and with a significantly higher serum creatinine (141 ± 114µmol/L) than in those patients without lesion progression (97 ± 44 µmol/L, P = 0.01). Lesion progression is more likely to occur in more severe stenoses.^7,8 Furthermore, the progression of renal artery stenosis is associated with a significant decline in renal function.³

Discussion Question 1 (continued):

• Role of treatment choice based upon the patient’s existing medical condition and comorbidities, i.e., renovascular hypertension with or without diabetes, chronic kidney disease, hyperlipidemia, peripheral vascular disease, coronary artery disease or left ventricular abnormalities

Response: Patients with diabetes mellitus are at increased risk for developing peripheral vascular disease and renal artery stenosis.⁹ Diabetic patients have more rapid progression of renal atherosclerotic disease toward critical stenosis or occlusion than their nondiabetic counterparts.⁷

Renal artery revascularization has been shown to stabilize or improve renal function in patients with significant renal artery stenosis and impaired renal function. However, some studies have suggested negligible or no benefit of renal function in diabetic patients with the same condition. Renal stents were placed in 17 diabetic and 33 nondiabetic consecutive patients with renal insufficiency (serum creatinine > 1.5 to 4.0 mg/dl) and bilateral stenosis or stenosis to a solitary (single) functioning kidney.¹⁰ At a mean follow-up of 36 ± 19 months following successful percutaneous renal revascularization, 79% of the nondiabetic patients (N = 26), and 76% of the diabetic patients (N = 13) (p=NS) demonstrated improvement in the slope of the reciprocal of serum creatinine, indicating improvement in renal function. The magnitude of the improvement favored the nondiabetic over the diabetic patients. Renal artery stenting appears to be equally beneficial in preserving renal function in diabetic and nondiabetic patients with ischemic nephropathy and global ischemia due to RAS. These data demonstrate that renal stent revascularization can delay the progression or improve renal dysfunction in selected diabetic and nondiabetic azotemic patients with ischemic nephropathy and bilateral or solitary kidney renal artery stenosis. Given the low procedural complication rate, and the beneficial long-term impact on renal function and blood pressure, renal stent revascularization is safe and effective therapy for the treatment of ischemic nephropathy in patients with or without diabetes mellitus. 10

Discussion Question 2: Discuss the ability to compare studies, perform meta-analyses and draw valid evidence-based conclusions based upon existing published definitions, measurement techniques, and criteria for reporting patient selection, methods and outcomes. Please specifically discuss:

• Definition of “ischemic nephropathy” and measurements of renal function by glomerular filtration rate, serum creatinine concentration and cystatin C.

Response: There is no universally agreed upon definition for “ischemic nephropathy”. The difficulty in defining this term speaks to the multiple pathologic mechanisms that result in end-stage renal disease, termed ischemic nephropathy. ''Impairment of renal function beyond occlusive disease of the main renal arteries'' has been offered as a general definition.¹¹ Deterioration of renal function in the presence of large vessel renal artery stenosis (RAS) may, or may not be related to renal hypoperfusion. Under normal conditions blood flow to the kidney is far in excess of metabolic needs, so that isolated modest renal artery narrowing would not be expected to cause end-organ ischemia due to hypoperfusion. Factors that are associated with irreversible dysfunction include 1) severe diffuse intrarenal atherosclerosis, 2) proteinuria > 1 gram / 24 hours (especially in a diabetic patient), 3) unilateral RAS with serum creatinine > 2.5 mg/dL, 4) renal resistive index > 80, and 5) marked atrophy of the renal cortex, although none of these factors is individually highly predictive of irreversible dysfunction. The pathophysiologic mechanisms of ischemic renal injury include; 1) hypoperfusion, 2) abnormal tubular dynamics, 3) derangements of tubular cell metabolism, 4) changes in tubular cell structure, and 5) tubular cell apoptosis. Clinical processes that could be related to these mechanisms include renal hypoperfusion due to main renal artery obstruction, renal atheromatous embolization, and small vessel renal atherosclerosis, all of which may contribute to the syndrome of “ischemic nephropathy”.

Atherosclerotic renal artery disease has been estimated to be the cause of end-stage renal disease (ESRD) in approximately 15% of patients over age 50 entering dialysis each year.^12-14 However, recent United States Renal Data System and Medicare data has demonstrated an alarming increase in patients with end-stage renal disease who have either a history of renal artery stenosis or prior therapy for atherosclerotic RAS.¹⁵ There is a general consensus that intervention to prevent loss of renal function should be performed before there has been a clinically evident decline in renal function. Successful implementation of this strategy requires an efficient and accurate method of screening for RAS in patients at risk for this disease.

The best predictor of improvement in renal function following percutaneous revascularization is a rapid rate of decline in renal function prior to intervention.¹⁷ The rapid decline in renal function reflected a more acute injury which was more likely to be reversible. A series of 32 patients (33 kidneys) with unexplained renal insufficiency and hemodynamically significant renal artery stenosis (only seven patients had unilateral RAS; the remainder had global renal ischemia) treated with renal artery stent placement demonstrated improvement or stabilization in renal function¹⁶ as measured by the slope of the reciprocal of the serum creatinine. The authors concluded that stent placement slowed the progression of ischemic nephropathy.¹⁸ A more recent study examined patients undergoing successful renal artery stent placement for bilateral or solitary renal artery stenosis (≥ 70%) with a baseline serum creatinine between 1.5 mg/dL and 4.0 mg/dL.¹⁹ Using reciprocal creatinine plots, all patients had deteriorating renal function as manifested by a negative slope. After revascularization, all had either changed to a positive or less negative slope, indicating improvement of renal function. A reversible component of ischemic nephropathy has been documented after percutaneous revascularization in multiple series.^18-20, (Rocha-Singh 2002#1012) In considering the results of percutaneous and surgical revascularization, most studies have classified serum creatinine as improved in 55%, unchanged in 25%, and worse in 20%.^18,20-24 Some clinicians assess serial changes in reciprocal serum creatinine or calculated creatinine clearance using the Cockroft-Gault formula, which support the beneficial effect of renal revascularization on ischemic nephropathy.^18-20 Analysis of the slope of reciprocal creatinine suggests that most patients have stabilization or slower progression of renal dysfunction, and a minority have long-term improvement. Potential explanations for failure of renal revascularization to improve renal function include underlying renal parenchymal disease that persists despite revascularization, revascularization-induced renal atheromatous embolization, radiocontrast-induced nephropathy, or acute tubular necrosis. Late decline in renal function most often is due to progressive glomeruloslerosis and less commonly failure of the revascularization (i.e. in-stent restenosis or bypass graft failure).

In properly selected patients, renal artery revascularization can stabilize or improve renal function. In one study, surgical revascularization resulted in significant improvement in postoperative total- and single- kidney glomerular filtration rate (GFR) as measured by nuclear scintigraphy.²⁵ Linear regression models suggested arrest of renal dysfunction manifest by a slower decline in GFR from 3.25% per week before surgery to 0.94% per week after surgery.²⁶ In other studies, stenting was associated with preservation of renal size after two years¹⁹. In a prospective observational study, medical therapy was associated with a decline in single kidney-GFR and total GFR, whereas stenting resulted in significant improvement in single kidney-GFR and total GFR²⁷. The most consistent predictor of improvement in renal function is the absence of parenchymal renal disease prior to intervention^20,28. Patients with ischemic nephropathy should be treated before the development of advanced renal failure. The best candidates for revascularization are those with baseline serum creatinine < 2.0 mg/dL, bilateral atherosclerotic RAS, normal renal resistive indices, and no proteinuria. In these patients, renal revascularization is best accomplished by stenting, although surgical revascularization may be considered in patients with concomitant severe aortic aneurysmal or occlusive disease. Patients with increased serum creatinine and unilateral renal artery stenosis, necessarily have renal impairment of the contralateral kidney since the non-obstructed kidney, is theoretically capable of compensating for the stenotic kidney. Consequently, in unilateral renal artery stenosis, the true impact of stent revascularization on renal function may be underestimated. Traditional teaching has been that ischemic nephropathy requires RAS of a solitary kidney or RAS involving bilateral kidneys. Several recent studies have challenged this conventional wisdom and suggest that revascularization of unilateral RAS can improve or stabilize renal function.

Revascularization of unilateral renal artery stenosis results in measurable improvement in the split-renal function of the stenotic kidney.^29,30 Restoring flow to the stenotic kidney reversed the hyperfiltration of the non- stenotic kidney resulting in a decreased proteinuria.³⁰ These data suggest that in patients with abnormal renal function, treatment of a hemodynamically significant unilateral RAS is beneficial in improving and/or stabilizing renal function.

Renal perfusion has traditionally been measured using nuclear scintigraphy.^31,32 More recently, electron beam computerized tomography,^33,34 positron emission tomography,³⁵ magnetic resonance,^36,37 and contrast enhanced Doppler ultrasonography have been used to assess renal blood flow.³⁸

Although renal angiography remains the gold standard for the diagnosis of renal artery stenosis, there is no objective angiographic method to assess renal perfusion. In the coronary circulation, the Thrombolysis In Myocardial Infarction (TIMI) frame count is an objective angiographic assessment of coronary blood flow that correlates with clinical outcomes.^{39 40} A surrogate measurement of renal blood flow is TIMI renal frame counts (RFC). It has been demonstrated in a small sample of patients that RFC’s were statistically prolonged in abnormal kidneys compared to normal controls suggesting that abnormalities in renal flow can be objectively measured using this technique. ⁴¹ The burgeoning field of proteomics offers several promising biomarkers associated with renal injury including Human Kidney Injury Molecule (KIM-1), -Glutathione S-Transferase (- GST), Urine ß-2 microglobulin, Urine - Glutathione S-Transferase (-GST).^42-45 These markers are related to specific components of the nephron, i.e., glomerulus, proximal tubule or distal tubule.

The diagnosis of renal ischemic injury includes reduced renal function and/or the detection of proteinuria. ⁴⁶ Renal insufficiency is best classified according to the estimated glomerular filtration rate (eGFR) calculated by the abbreviated MDRD formula that requires age, gender, race and serum creatinine. ⁴⁷ An eGFR below 60 ml/min/1.73 m2 indicates chronic renal disease stage 3, whilst values below 30 and 15 ml/min/1.73 m2 indicate chronic renal disease stages 4 and 5, respectively. Another commonly used formula (the Cockcroft–Gault equation) estimates creatinine clearance based on age, gender, body weight and serum creatinine. ⁴⁸ This formula is valid in the range 60 ml/min, but it overestimates creatinine clearance in chronic kidney disease stage 3 to 5. Both formulae help to detect mild impaired renal function in the face of serum creatinine values that are still in the normal range. A reduction in glomerular filtration rate and an increase in cardiovascular risk may also be inferred from the increased serum levels of cystatin C. ⁴⁹ Cystatin C is a non-glycosylated basic protein with a low molecular mass that is freely filtered by the glomerulus. ⁵⁰ It is produced by all nucleated cells in the body at a constant rate and is not metabolized in the serum. Cystatin C levels are independent of age, gender and muscle mass. ⁵¹ Studies show that it may be a better marker of glomerular filtration rate (GFR) than creatinine. ⁵²

Discussion Question 2 (continued):

• Definitions for “uncontrolled”, “resistant” and “severe” hypertension

We suggest the standard definitions described in the Seventh Report of the Joint National Committee on the Prevention, Detection, Evaluation and Treatment of High Blood Pressure⁵³ and the Peripheral Arterial Guideline document published by the American College of Cardiology and the American Heart Association ⁵⁴ be used:

• Resistant (refractory) hypertension is 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 ⁵³.
• Uncontrolled hypertension is defined as BP above goal. ⁵³
• Severe hypertension is defined as Stage 2 hypertension with systolic blood pressure ≥ 160 mm Hg or diastolic blood pressure ≥ 100 mmHg. ⁵³
• Accelerated hypertension (sudden worsening of previously controlled hypertension). ⁵⁴
• Malignant hypertension (hypertension with coexistent evidence of end-organ damage, including left ventricular hypertrophy, congestive heart failure, visual or neurological disturbance, and/or advanced (grade III-IV) retinopathy). ⁵⁴

Discussion Question 2 (continued):

• Measurements and uniform thresholds for BP - systolic, diastolic, mean, ambulatory and office BP in elderly Medicare patients

The measurement of hypertension requires a standardized approach as described in the Seventh Report of the Joint National Committee on the Prevention, Detection, Evaluation and Treatment of High Blood Pressure⁵³:

• “Persons should be seated quietly for at least 5 minutes in a chair (rather than on an exam table), with feet on the floor, and arm supported at heart level. Caffeine, exercise, and smoking should be avoided for at least 30 minutes prior to measurement. An appropriately sized cuff (cuff bladder encircling at least 80 percent of the arm) should be used to ensure accuracy. At least two measurements should be made and the average recorded.” “…the cuff should then be inflated 20–30 mmHg above this level for the auscultatory determinations; the cuff deflation rate for auscultatory readings should be 2 mmHg per second. SBP is the point at which the first of two or more Korotkoff sounds is heard (onset of phase 1), and the disappearance of Korotkoff sound (onset of phase 5) is used to define DBP. Clinicians should provide to patients, verbally and in writing, their specific BP numbers and the BP goal of their treatment.” ⁵³
• Optimal blood pressure is < 120/80 mmHg. Prehypertension is defined as 120-139/80- 90 mmHg. Hypertension is defined as ≥ 140/90 mmHg. ⁵³

Discussion Question 2 (continued):

• Imaging methods, uniform thresholds and translesional gradients for “critical”, “severe” and “hemodynamically significant” RAS

Response: Nuclear scintigraphy with captopril is an unsatisfactory screening test for RAS. ⁵⁴ The accuracy of this test is suboptimal when there is bilateral RAS or azotemia. Given that >50% of patients with atherosclerotic RAS have bilateral disease or azotemia, these are serious limitations. When captopril renography was compared to catheter angiography in a clinical practice setting, the sensitivity was only 74% and the specificity was only 59%. ⁵⁵ Several investigators have demonstrated the validity of renal artery Doppler ultrasonography (duplex) to diagnose RAS. In one prospective series, 29 patients (58 renal arteries) underwent duplex ultrasonography and contrast arteriography. The sensitivity of renal artery duplex ultrasonography was 84%, specificity of 97%, and positive predictive value of 94% for a detection of > 60% stenosis ⁵⁶. Utilizing criteria of peak systolic velocity within the renal artery >180 cm/sec, duplex ultrasonography was able to discern between normal and diseased renal arteries with sensitivity of 95% and specificity of 90% ⁵⁷. The ratio of peak systolic velocity (PSV) in the area of RAS compared to the PSV within the aorta (Renal to Aortic Ratio (RAR)) of >3.5 predicts the presence of >60% RAS. Using this criterion, renal artery duplex demonstrated a sensitivity of 92%.

In a large prospective series of 102 consecutive patients who underwent both duplex ultrasonography and contrast arteriography within one month of each other, 62 of 63 arteries with < 60% stenosis, 31 of 32 arteries with 60-79% stenosis, and 67 of 69 arteries with 80-99% stenosis were correctly identified by duplex ultrasonography. Occluded renal arteries were correctly identified by ultrasonography in 22 of 23 cases. The overall sensitivity of duplex ultrasonography was 98%; specificity 99%; positive predictive value 99%; and negative predictive value 97%⁵⁸. Limitations of ultrasound imaging of the renal arteries include large body habitus and overlying bowel gas obscuring identification of the renal arteries. In a retrospective series of patients who underwent independent core lab analysis of duplex ultrasonography and quantitative arteriography, of 67 renal arteries studied, the finding of a renal:aortic systolic velocity ratio of >2.5 was the most accurate duplex-based criterion for >60% stenosis. ⁵⁹ However, several multicenter prospective trials have demonstrated the utility of renal artery duplex ultrasonography to demonstrate the status of renal arteries both de novo and after stent revascularization. ⁶⁰

Magnetic resonance arteriography (MRA) is a useful non-invasive diagnostic test to identify RAS. Minimally invasive and requiring only a peripheral intravenous cannula, the results of renal MRA have been impressive⁶¹. Correlation with arteriography has varied based on equipment, technique, and the skill of the interpreter⁶². However, approximately 10% of patients cannot undergo MRA due to implanted metal (i.e. permanent pacemakers) or claustrophobia. In patients who have undergone renal revascularization with metallic stents, MRA cannot be used to determine patency of the stent due to signal dropout from the metallic stent. Finally, recent reports suggest a potentially fatal complication of gadodiamide, the commonly used MR-imaging agent, in patients with compromised renal function resulting in nephrogenic systemic fibrosis⁶³.

Computerized tomographic arteriography (CTA) has recently demonstrated its’ efficacy in diagnosis of renal artery stenosis. In a recent prospective evaluation of CTA compared to digital subtraction angiography in 50 consecutive patients, the sensitivity, specificity and accuracy to diagnose RAS was 100%, 98.6%, and 96.9% respectively. ⁶⁴ Hemodynamically significant RAS is defined as: 1) 50% to 70% diameter stenosis by visual estimation with a peak translesional gradient (measured with a ≤ 5 Fr. catheter or a 0.014-in. pressure wire) of ≥ 20 mmHg or a mean gradient ≥ 10 mmHg; 2) any stenosis greater than or equal to 70% diameter stenosis ; or 3) ≥ 70% diameter stenosis by intravascular ultrasound measurement. ^{54, 65}

Discussion Question 2 (continued):

• Impact of heterogeneous patient presentation, disease progression and limited understanding about the current natural history of atherosclerotic RAS upon appropriate inclusion and exclusion criteria for clinical trials

Response: Most natural history studies reported in the literature are retrospective studies. The rates of RAS progression range from 36% to 71% 66. Serial duplex ultrasound studies in patients with RAS confirmed that lesion progression to occlusion only occurred if baseline atherosclerotic RAS was > 60% 7. A recent randomized trial of hypertensive patients, with lesions ≥ 50%, demonstrated that 16% of the medically treatment group progressed to occlusion at one-year ⁶⁷. Scoble et al 13 found that atherosclerotic renovascular disease was the cause of end stage renal disease (ESRD) in 14% of patients starting dialysis therapy. Mailloux and colleagues⁶⁸ reviewed the causes of ESRD in 683 patients over 20-years. Eighty-three patients (12%) had documented RAS as a cause of ESRD. Since these investigators only performed arteriography in patients in whom they highly suspected RAS, it is likely that the true incidence of RAS as a cause of ESRD was seriously underestimated. A recent study reported that 16% of 49 patients starting renal replacement therapy had > 50% bilateral RAS or RAS to a single functioning kidney⁶⁹. RAS should be searched for in every patient starting dialysis if a clear-cut etiology for the ESRD is uncertain^70-72.

Discussion Question 2 (continued):

• Use of intermediate/surrogate outcomes (BP improvement or number of medications) versus hard health outcomes (mortality, decreased MI, stroke or CHF)

Response: The relationship between hypertension, stroke, myocardial infarction, and cardiovascular death are well known. ^73,74 Therefore, objective reports of improvements in systolic and diastolic blood pressure are valid and important surrogate endpoints for health outcomes. Multiple studies have also demonstrated that minimal-mild reduction in blood pressure result in major reductions in hard cardiovascular endpoints (i.e. stroke, myocardial infarction, cardiovascular-related mortality). ⁷⁵

Discussion Question 2 (continued):

• Causal attribution of treatment outcomes to renal artery interventions, in view of variable pre- and post-procedure medications and changing best medical treatment since the introduction of ACEIs, ARBs, statins and new direct renin inhibitor (aliskiren)

Response: Patients being treated for refractory hypertension are already on these medications, with improvement from revascularization apparent and temporally linked to PTRAS. However, no standard medical therapy regimen has been formally established for patients with renal artery stenosis due to atherosclerosis. Strategies for medical therapy have been adapted from the coronary and cerebrovascular disease management literature, including the use of antiplatelet therapy (mainly aspirin), antihypertensive therapy, lipid-lowering therapy (aiming for NCEP-ATP III goals of LDL- cholesterol levels control, and tobacco cessation.

Discussion Question 2 (continued):

• Current state of primary surgical correction and surgical renal artery reconstruction following stenting

Response: Surgical treatment is neither a common nor preferred option for treating RAS. Surgery has been relegated to patients already undergoing major abdominal surgery, such as abdominal aortic aneurysm repair. In the 1980’s and early 1990’s, before the refinement of renal artery stent deployment, there were many surgeons performing renal artery surgical revascularization. However, even in published series of renal artery surgery by the experts in the field, the perioperative mortality rate ranged from ~3-9 %. ⁷⁶ The number of surgical renal revascularization cases have dwindled in the United States, largely supplanted by endovascular revascularization, suggesting that adequately trained vascular surgeons whose results will be able to match those found in the medical literature will be few and far between. Surgical renal revascularization is largely of historical interest in most medical centers.

Discussion Question 2 (continued):

• Variable experience of interventionalists plus evolution of stents and embolic protection devices

Response: There is no data to compare outcomes with the experience or skill of the interventionalist for PTRAS. However, in virtually every publication evaluating outcomes related to skill of the practitioner, those with the greatest experience possess the best outcomes. This has been shown in the management of coronary artery disease, for example, comparing management of unstable coronary syndromes between general internists and cardiologists.

Several mechanisms are implicated in the post- procedural decline in renal function that occur in a subset of patients following renal artery stenting, including contrast-induced nephrotoxicity and atheromatous embolization. This has led to interest in embolic protection devices to capture embolic debris that might be liberated during stenting. Recent studies suggest that embolic protection was associated with trends towards improvement in renal function when contrasted against historical controls^77-79. However, these devices increase procedural complexity and their effectiveness is not established.

In the largest published single center prospective series, 63 patients had 83 renal arteries treated with renal artery stenting with embolic protection⁸⁰. All patients had baseline renal dysfunction with an eGFR < 60 cc/min (24% had an eGFR < 30 cc/min) and evidence of deterioration in renal function for six months prior to intervention. Sixty percent of the filter baskets had gross evidence of macroscopic debris. Six months after intervention, 97% of patients had stabilization or improvement in renal function.

The first multicenter randomized trial of renal artery atheroembolic protection for preservation of renal function during renal artery stenting was very recently presented at the American College of Cardiology 2007 meeting in New Orleans. This study, which evaluated changes in renal function, is the first to suggest that emboli protection devices used in combination with parenteral antiplatelet therapy (glycoprotein IIb/IIIa inhibitors) improves renal function outcomes in patients undergoing stent revascularization.

Discussion Question 2 (continued):

• Role of an adequately powered RCT evidence-based process versus general agreement or consensus processes

Response: Randomized clinical trials do not always reflect “real-world” clinical practice as they select ideal patients for entry. There would be valuable information gained from “cohort” controlled trials and patient registries with more liberal entry criteria. Surgical procedures, including endarterectomy, aorto-renal bypass, or extra-anatomic bypass, are effective methods for renal artery revascularization in selected patients.^19-23 The risk of surgery increases in patients who require concomitant aortic reconstruction, patients with renal insufficiency, and when aortic grafts are used as a source of the bypass graft. The five-year outcomes for surgical therapy demonstrate graft failure in 6% to 18%, the need for reoperation in 5% to 15%, and five year survival in 65% to 81%.^18-21 Surgery has been compared to balloon angioplasty for renal artery revascularization in a randomized clinical trial in hypertensive patients with atherosclerotic renal artery stenosis.²² At the two-year follow-up interval, the surgery group had a higher primary patency rate compared to the balloon angioplasty group (95% vs. 75%, P = 0.05), however there was no difference in the secondary patency rate between the groups (balloon 90% vs. surgery 97%, P = 0.61). The clinical endpoints of hypertension control and renal function preservation were not different for angioplasty or surgery. Major complications occurred twice as often in surgical (34%) patients when compared to balloon (17%) angioplasty patients. The authors concluded that in patients who were candidates for either surgery or balloon angioplasty for renal artery stenosis, balloon angioplasty should be the first choice of therapy. Stent placement has consistently proven superior to balloon angioplasty in the treatment of renal artery atherosclerotic lesions. Balloon angioplasty was compared to stent placement in atherosclerotic renal artery stenoses by Dorros and coworkers.²³ Quantitative vascular angiography (QVA) and translesional pressure gradients were measured in 18 patients who served as their own controls. Stents were significantly more effective than balloon angioplasty in these atherosclerotic renal artery lesions.

Discussion Question 3: For both state-of-the- art PTRA with stenting (PTRAS) utilizing embolic protection and surgical renal artery reconstruction (RAR), please specifically discuss:

• Diagnostic tests or baseline patient characteristics that accurately predict post- treatment renal function outcomes

Response: The renal fractional flow resere (FFR), is an assessment of the severity of the RAS using maximal vasodilation with papaverine, an endothelium independent vasodilator. There is a poor correlation between quantitatively measured renal angiographic stenosis and hemodynamic parameters, but an excellent correlation between renal FFR and the baseline pressure gradient ⁸¹. Angiographic evaluation of aorto-ostial renal artery stenosis is limited by the inaccuracy of visual estimation in these moderately large vessels, the difficulty in obtaining orthogonal views of the stenosis, and difficulty establishing the normal reference segment of the renal artery. Other characteristics of the stenosis such as length and geometry (i.e. eccentric lesions), in addition to the diameter stenosis, contribute to restriction of blood flow. These factors cumulatively contribute to the poor correlation between angiographic and hemodynamic parameters of lesion severity.

Renal FFR was measured in 17 patients with uncontrolled hypertension. ⁸² A beneficial blood pressure response to renal stent placement was seen in 86% of those patients with an abnormal baseline renal FFR (< 0.8) compared to 30% in the normal FFR group. Interestingly, the translesional pressure gradient (resting, peak systolic, and hyperemic), did not separate blood pressure responders from non-responders. The sensitivity for an abnormal renal FFR to predict an improvement in BP control after renal stenting was 88%. ⁸²

The second method of improving patient selection for renal artery revascularization is to measure a biomarker, such as brain natriuretic peptide (BNP), that is related to renovascular hypertension. ⁸³ Brain natriuretic peptide (BNP) is a neurohormone released from ventricular myocytes under conditions of cell stretching. It promotes diuresis, natriuresis, arterial vasodilation, and antagonizes the renin angiotensin system and angiotensin II. ⁸⁴ BNP has also been shown to be synthesized and released from glomerular mesangial and epithelial cells. ⁸⁵ Hemodynamically significant renal artery stenosis is known to promote activation of the renin-angiotensin system leading to increased levels of angiotensin II. In animal experiments angiotensin II has been shown to induce synthesis and release of BNP, and that BNP mRNA is up-regulated with RAS. ^86,87 It would appear that angiotensin II, directly stimulates the synthesis and release of BNP independent of cardiac cell stretching and that the BNP mRNA is up-regulated in the two-kidney, one clip renal artery stenosis model. 8^6,87

Patients with uncontrolled hypertension who had visually estimated significant atherosclerotic renal artery stenosis (≥ 70% diameter stenosis) by contrast angiography had BNP sampled. ⁸⁸ Patients with other medical conditions associated with elevated BNP levels (congestive heart failure, acute coronary syndromes and renal failure) were excluded. Procedure success, defined as a ≤ 30% residual diameter stenosis without a serious complication following renal stent placement, was obtained in all of the patients. For the entire group, hypertension was cured or improved in 70% (19 of 27) of the patients at hospital discharge. Twenty-two (81%) patients with RAS had a baseline BNP > 80 pg/mL. In this group with elevated BNP, hypertension improvement occurred in 77% (17/22), compared to none of the five patients with a baseline BNP  80 pg/mL (P = 0.001). If the post-treatment BNP fell > 30%, 94% (16 of 17 patients) improved their blood pressure control. If the post-stent BNP fell by ≤ 30%, only one patient (10%), experienced improved blood pressure control (P < 0.001). ⁸⁸ Preliminary data suggest that BNP is increased in patients with refractory hypertension and renal artery stenosis, and that this peptide may be useful to predict which patients will clinically improve their blood pressure after successful renal revascularization. An elevated baseline BNP > 80 pg/mL strongly correlated with hypertension improvement after 3.5 months of follow-up.

Discussion Question 3 (continued):

• Subgroups of Medicare patients with atherosclerotic RAS who clearly and consistently benefit from either PTRAS with embolic protection or surgical RAR

Response: There are no FDA approved indications for emboli protection devices in the renal arteries. Although there is one report of objective evidence of possible benefit of renal PTRAS with embolic protection, the data are unconfirmed. There are inherent disadvantages and potential risks of emboli protection devices. These include the possibility for distal renal artery injury, dissection, or spasm, and lack of support for stent delivery that is available with dedicated renal guidewires. At present, none of the filter devices has been developed specifically for the renal artery, and using coronary equipment may occasionally lead to undersizing of the filter. ⁸⁹

There is no available surrogate biomarker, such as troponin for the heart, to detect renal embolic injury. The evidence for atheroemboli associated with carotid intervention and manipulation of the plaque has been well documented with non-invasive studies. ⁹⁰ It is likely that the same is true for renal arteries. ⁹¹

Henry and coworkers placed renal stents in 65 renal arteries in 56 patients using emboli protection devices.⁹² They noted debris retrieval following renal stent deployment in 100% of the patients with distal balloon occlusion (Percusurge [n = 38], Medtronic, MN), and in 80% of the filter cases (FilterWire [n = 26], BSC, Natick, MA and Angioguard [n = 1], Cordis, Miami, FL). Particulate analysis demonstrated atheromatous debris measuring 201 ± 76 µm in diameter. Interestingly, there was no difference in the size or number of particles regardless of whether balloon pre-dilation was performed or not. there were two episodes of renal artery spasm, relieved with vasodilators. There were no dissections or major complications related to the use of the protection device. Holden and colleagues also reported a retrospective series involving 46 renal stents and 37 patients who had abnormal renal function. 78 This group used the Angioguard filter device and found visible debris present in 65% of the cases.

The recently begun NHLBI funded CORAL trial, comparing best medical therapy to renal intervention, has abandoned mandated use of emboli protection in renal stent patients.

Discussion Question 3 (continued):

• Risks of complications for patients (particularly the older Medicare population) with progressive renal dysfunction and multiple comorbidities, especially the risk of post- treatment worsening renal function and hastening of dialysis

Response: In a meta-analysis, Isles and coworkers determined that in patients with abnormal renal function who undergo renal artery stent placement, roughly one-quarter improve their renal function, one-quarter worsen their renal function, and one-half remain unchanged. The two most likely reasons for deterioration of renal function after intervention are contrast induced nephropathy and atheroembolization. The bulky aorto-ostial plaque is a likely source of emboli, but the incidence has been difficult to determine.

Conclusion The data surrounding atherosclerotic renal artery disease is quite vast, however, prospective multicenter prospective trials are lacking. Despite this limitation, it does appear that patients with refractory or resistant hypertension; global renal ischemia on the basis of renal artery stenosis; renal artery stenosis in the face of baseline azotemia (i.e. serum creatinine ~2.0 mg/dL; dialysis-dependent renal failure due to renal artery stenosis, particularly in those patients with rapid deterioration in renal function; and recurrent pulmonary edema or unstable angina pectoris due to renal artery stenosis obtain measurable benefit from renal artery stent revascularization. Due to the vast improvement in technology, the widespread adoption of endovascular over surgical revascularization, and the aging of the population, we urge CMS to maintain current coverage determinations for renal artery stent revascularization. We support active enrollment in the CORAL trial for appropriate patients, are gratified that the CORAL trial is meeting its current enrollment quotas and suggest potential revisions of this policy once the CORAL trial data has been reviewed, analyzed, and reported. We appreciate the guidance of Dr. Christopher White, M.D., F.S.C.A.I. who was the lead author on this document, with assistance from Michael R. Jaff, D.O. The contact person for at SCAI regarding this issue is Wayne Powell and he may be reached at (202) 375-6341 or wpowell@scai.org. SVMB’s contact person is Greg Schultz, Executive Director and he may be reached at (847) 480-2961 or gschultz@svmb.org. Sincerely,

Bonnie Weiner. M.D., FSCAI
President, Society for Cardiovascular
Angiography and Interventions.

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The National Kidney Foundation (NKF) appreciates the opportunity to submit comments on the proposed National Coverage Decision (NCD) memo for Percutaneous Transluminal Angioplasty (PTA) and Stenting of the Renal Arteries (CAG-00085R4).

We recognize that there are no published randomized controlled clinical trials comparing angioplasty with stent placement to aggressive medical therapy. The latter usually includes some combination of anti-hypertensive drugs, a statin, and anti-platelet agents. The recent AHRQ literature review identified only two studies of reasonable quality, which compared renal artery angioplasty without stenting to aggressive medical therapy. Furthermore, while there is some evidence of a relative benefit in reducing blood pressure after angioplasty in patients with bilateral disease, available medical evidence does not support the use of one treatment option over another.

Nevertheless, renal artery PTA with stent placement across the stenosis is currently the invasive procedure of choice for atherosclerotic renal artery lesions. The American College of Cardiology/American Heart Association published 2005 guidelines for the management of patients with peripheral arterial disease that provide recommendations about which patients should be considered for renal artery revascularization. According to the National Kidney Foundation (NKF) clinical practice guidelines on Hypertension and Antihypertensive Agents in Chronic Kidney Disease, decision-making about specific therapy for renal artery disease requires balancing the potential benefits versus complications of a planned strategy or intervention.

In order to preserve clinical decision making, the NKF supports the proposed decision memo dated November 20, 2007, to make no change in the NCD addressing PTA and stenting of the renal arteries. The CMS reimbursement policy should continue to allow coverage for renal artery PTA and stenting until further data is available to guide clinical decision making.

Given the uncertainty in the optimal treatment for renal artery atherosclerotic lesions, the NKF supports clinical research that compares aggressive medical therapy versus revascularization with medical therapy. The results of the NIH-sponsored Cardiovascular Outcomes in Renal Atherosclerosis Lesions (CORAL) trial, anticipated by approximately 2010, offer the most promise to provide additional information comparing aggressive medical therapy to intervention.

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December 18, 2007

Steve Phurrough, MD, MPA
Director, Coverage and Analysis Group
Centers for Medicare & Medicaid Services
Room C1-13-18
Mail Stop C1-09-06
7500 Security Boulevard
Baltimore MD 21244-1850

***Comments submitted electronically via CMS Web site, http://www.cms.hhs.gov/mcd/viewdraftdecisionmemo.asp?id=202 and Email, Steve.Phurrough@cms.hhs.gov respectively***

RE: NCA for Percutaneous Transluminal Angioplasty (PTA) and Stenting of the Renal Arteries (CAG-00085R4) November 20, 2007

Dear Dr. Phurrough:

The Society of Interventional Radiology (SIR) is a physician association with over 4,300 members that represents the majority of practicing vascular and interventional radiologists in the United States. SIR commends the Centers for Medicare & Medicaid Services (CMS) for the recent proposal to uphold the current national coverage policy for Percutaneous Transluminal Angioplasty (PTA) and Stenting of the Renal Arteries (CAG-00085R4); ensuring continued access to patients. SIR is pleased that CMS will uphold the previously established decision that provides reimbursement for patients for “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”. SIR supports that the determination of the appropriate treatment option is best made by the treating physician.

While we sympathize with the intentions, we request omission of paragraphs in section VIII, “CMS Analysis”, including

“CMS recommends that for all renal artery revascularization procedures, whether performed within or outside of RCTs or other clinical research studies, informed patient consent should be obtained which:

Accurately explains the purpose and duration of the study, its procedures, potential risks and benefits, treatment alternatives (i.e., medical therapy alone versus combined medical therapy plus endovascular and/or surgical co-interventions), need for long term follow-up, as well as any financial or intellectual conflicts of interest, such that a patient understands this information and its relevance to his or her own clinical situation, and can make a voluntary decision whether to enroll and continue to participate; and

Discloses to prospective Medicare patients the following relevant information:

The May 2004 FDA Class I recall (a situation in which there is reasonable probability that use of or exposure to a violative product will cause serious adverse health consequences or death) for a transhepatic biliary stent, which noted that vascular use of these stents has not been cleared by the FDA and which strongly recommended that physician use of these stents be limited to FDA-approved uses only;

The July 2007 MedCAC panelists determination that there is overall uncertainty about: a) the adequacy of the evidence to draw conclusions about safety and clinical effectiveness of surgical and endovascular renal artery interventions for the treatment of patients with atherosclerotic RAS; b) the applicability of published results to Medicare patients with typical comorbidities, providers (facilities/physicians) in community practice, and patient subgroups not represented in published studies; and c) whether there are any improved key health outcomes attributable to surgical and endovascular co-interventions as compared to medical treatment alone; and

Availability of CMS’s decision memorandum for renal artery revascularization procedures to be read and discussed by Medicare patients and their physicians at: http://www.cms.hhs.gov/mcd/viewtrackingsheet.asp?id=202.”.

SIR believes that discussion of these issues are best left to the judgment of the treating physician, and in fact for many or most patients will be confusing and anxiety-provoking. In our opinion, it is impossible for most lay people to put these issues in context, and is an unnecessary intrusion into the physician-patient relationship.

SIR appreciates CMS efforts in garnering input from the physician community regarding this issue. SIR stands ready to participate in any future proceedings regarding this issue and looks forward to the emergence of new evidence as it becomes available from the randomized trials now underway.

If SIR can be of any assistance now or in the future regarding the evaluation of minimally invasive interventional radiology procedures such as percutaneous transluminal angioplasty (PTA) and stenting of the renal arteries, please do not hesitate to contact Tricia McClenny, Associate Executive Director or Dawn R. Hopkins, Director of Reimbursement & Health Policy at the SIR office (703) 691-1805 or by email at McClenny@SIRweb.org or Hopkins@SIRweb.org, respectively.

Sincerely,

[Endorsed copy in .Pdf format submitted to email addresses detailed on page 1]

David Sacks, MD President

CC: Marcel Salive, MD, MPH, CMS
Sarah McClain, MHS, CMS
J. Lawrence Schott, MD, MS, CMS
John Kaufmann, MD, SIR
Peter B. Lauer, CAE, SIR
Michael E. Edwards, MD, SIR
Richard A. Baum, MD, SIR
Sean Tutton, MD, SIR
Gary Siskin, MD, SIR
Katharine L. Krol, MD, SIR
Harvey Neiman, MD, ACR
Anita Pennington, ACR
Tricia McClenny, MD
Dawn R. Hopkins, SIR

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I read with interest the position that CMS is taking on RAS. I am a simple interventional cardiologist blessed with access to world class facilites in rural Arizona. Though our hosptial is not engaged in leading edge research, it takes care of people. I would agree that treatement of hypertension is rather complex. However, in selected cases, RAS is the cause of the patient''s hypertension. As a clincian it is very difficult to tell a patient who is having side effects from three to six BP meds, to simply continue taking them and in most cases increase the doses. I feel it is incumbent to assess for RAS and if found to consider revascularization. When I have performed PTA with or without stenting (usually for persistent gradient or disection), in these selected cases, I can tell you it works. The BP is controlled on fewer agents, rarely no agents. The patients are helped. I suppose if you are in Boston, as I was for five wonderful years of training, and can enroll patients in RCT, I would, as suggested by CMS. Here in Arizona, that is not a viable option. To take away a line of therapy that works, when applied correctly, is inappropriate. Maybe others are not as "careful" as I have been in patient selection, however as a front line physician I can tell you with certainty to throw out the baby with the bathwater serves no one''s interest. Please consider the path CMS is headed with care.

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I am a vascular surgeon practicing both open surgical and percutaneous endovascular treatment of renal artery stenosis. I feel coverage should be limited to outcomes-based indications. Unfortunately there are few randomized trials however general consensus suggests: Patients presumed to have renovascular hypertension should fit into high risk groups for this disease, and have documented failure of medical therapy(>3 drugs) or the presence of significant end-organ manifestations despite medical therapy. In addition, for ischemic nephropathy treatment (percutaneous or surgical) should be reserved to criteria as suggested in:

Management of ischemic nephropathy: dialysis-free survival after surgical repair. J Vasc Surg. 2000 Sep;32(3):472-81; discussion 481-2.

Percutaneous treatment of renal artery stenosis should be cautiously applied to diabetics,those with mild hypertension, or patients not appropriately managed medically.

Consideration for use of embolic protection devices should possibly be included in any payment decision, particularly in light of:

Distal embolic protection during renal artery angioplasty and stenting. J Vasc Surg. 2006 Jul;44(1):128-35.

And awaiting completion of clinical trials to examine their use.

Thank you.

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