September 30, 2008

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

Re: Potential national coverage determination (NCD) topics

Dear Dr. Phurrough:

Boston Scientific Corporation appreciates the opportunity to present these comments responding to the list of potential NCD topics posted by the Centers for Medicare & Medicaid Services (CMS) on July 30, 2008.

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, including those treating cardiovascular and electrophysiological conditions.

As a result, we are particularly interested in CMS’ NCD process and we have submitted many comments to CMS in response to specific coverage proposals on a wide range of treatments involving less invasive and innovative technologies. We appreciate CMS’s identification of specific topics that it may consider for potential initiation of an NCD in a transparent process that allows comments from stakeholders on the appropriateness of initiating coverage reviews.

Our comments will cover three areas: First, our overarching considerations on NCDs; second, submissions on three separate topics of particular interest to BSC; and third, we offer some process questions for CMS as the agency considers additional future topics.

Generally, we believe that initiating an NCD review is best reserved for those instances when significant variation exists between actual medical practice and evidence-based guidelines of physician specialty societies. We also believe that NCDs are better suited for those cases in which local coverage determinations (LCDs) diverge and the misalignment of these LCDs leads to significant variability in treatments among similarly situated Medicare patients.

We also believe that NCDs are ideally opened when new evidence emerges that indicates a serious or potentially serious safety issue for Medicare patients. Generally, safety issues should be viewed within the context of treatment alternatives, and consideration of them should take into account the varying clinical outcomes often associated with treating patients of varying complexity and co-morbidities.

We support reconsiderations of negative NCDs when new clinical outcomes data is available that suggests improved health outcomes resulting from the non-covered item or service. The prospect of expanding and contracting coverage based on the latest evidence is appropriate and ensures that Medicare patients obtain care reflecting up-to-date practice, specialty consensus and clinical evidence.

Proposed NCD Topics of Particular Interest
Boston Scientific is particularly interested in three topics that CMS listed for potential consideration. In the appendices to this letter, please find our more detailed comments on three following topics from the July 30, 2008 List of Potential Topics.

1. Off-label use of drug-eluting coronary stents,
2. Peripheral arterial stenting and vascular intervention, and
3. Ablation for atrial fibrillation.

For each of the respective topics, we present a review of the underlying disease state, an assessment of the evidence, and a review the evolution of the treatment. We focused on these three topics exclusively because of our familiarity with these treatments (as noted above, we manufacture medical devices used in these treatments). Because of physician consensus, established medical practice, the large volume of published and presented data, and additional studies in the pipeline, we believe pursuing an NCD for any of these three topics would be premature, and therefore request that CMS place a low priority on setting NCDs for these treatments.

BSC’s Questions for CMS
In the spirit of transparency CMS has shown by offering a list of topics for which CMS might initiate coverage reviews, we present a series of questions that we hope CMS may be able to address, perhaps in conjunction with its next posting of additional topics.

1. Is CMS using the Medicare Evidence Priorities list as guidance in determining what treatments or topics may be ripe for NCD review?
2. CMS has previously stated that it plans to issue a list of potential topics on a quarterly basis. Is that still the agency’s intent?
3. Will all internally-generated NCD topics now be preceded by the posting of the topic on the potential topics list? If CMS removes a topic from the list, may we assume that CMS will not initiate a NCD review on this topic without again posting it?
4. How will CMS prioritize the topics for which CMS plans to initiate NCD reviews?
5. Will CMS use the guidelines of professional medical organizations in determining what NCDs to pursue?

6. Based upon comments of stakeholders, new data and other sources, will CMS specify those topics for which it has considered NCD review but will opt to hold off on consideration? That is, will CMS formally announce the removal of a topic from the list?

In closing, Boston Scientific applauds CMS efforts to be transparent in deciding what specific topics to potentially initiate NCD reviews.

We believe that CMS should consider focusing its resources on conducting NCD reviews in areas with substantial variation of LCD policies and for which treatments and therapies lack specialty society consensus and pose safety risks for patients. Consequently, we believe CMS should place low priority on opening an NCD on the three topics cited above.

However, if CMS finds that its review of the evidence suggests that an NCD may be appropriate for any of the three topics we discuss, we would appreciate an opportunity to meet with CMS before a decision is made to formally open up an NCD. Such a meeting would provide CMS with more detailed and nuanced discussion and review of the clinical outcomes evidence. We believe that such a discussion would be helpful in CMS’ decision-making.

We thank you for your consideration, and appreciate your consideration of our overall perspectives as well as the latest evidence on the three key topics presented in these comments.

Sincerely,

Parashar B. Patel
Vice President, Health Economics and Reimbursement
Boston Scientific Corporation

CMS listed “Off label use of drug eluting coronary stents” as one of the topics for which CMS is seeking comments. Specifically, CMS requested comments on the available evidence specifying patient groups that do or do not benefit from treatment with coronary stents. Fortunately, bare metal stenting (BMS) and drug-eluting (coronary) stenting (DES) are probably one of the most studied therapies available to Medicare beneficiaries. This data has been utilized by the American College of Cardiology (ACC), Society for Coronary Angiography and Interventions (SCAI) and the American Heart Association (AHA) to create, and update with current data, practice guidelines which address the appropriate utilization of coronary stenting procedures.

The guidelines, updated in December 2007 recognize that, “DES should be considered as an alternative to the BMS in subsets of patients in whom trial data suggest efficacy.” They also recognize extended use applications: “DES may be considered for use in anatomic settings in which the usefulness, effectiveness, and safety have not been fully documented in published trials.” (58) It is clear from the current data and practice guidelines that the specialty societies and national voluntary health organizations believe that off label patient populations can appropriately receive coronary stents. We also note that the flow of evidence on the use of coronary stents will continue, allowing CMS to determine, in the future, whether an NCD for coronary stenting therapy should be initiated.

While there has been attention on the benefits and risks of coronary stenting, and there will always be healthy discussion about the role of any therapy, by and large the role of coronary artery stents in treating coronary artery disease is fairly well agreed upon. This extends to off label usage as well.

For example, a study called SCAAR (Swedish Coronary Angiography and Angioplasty Registry), a national registry in Sweden consisting of twenty-six centers, used registry data to compare the role of BMS and DES. While the one year follow-up results showed an increased rate of DES-related very late stent thrombosis (vLST) generating tremendous attention and concerns about DES safety, those concerns have largely been eliminated by virtue of additional SCAAR data following the same patients for 2-3 years. This data showed that there was no difference in thrombosis or other safety endpoints between DES and BMS (34).

In one highly publicized study, the investigators for the Clinical Outcomes Utilizing Revascularization and Aggressive Drug Evaluation (COURAGE) trial (77), presented data detailing the results of their work to establish whether percutaneous coronary intervention (PCI) can provide an incremental quality of life benefit to patients with chronic coronary artery disease over that provided by optimal medical therapy. While this study generated significant headlines, and health professionals debated (and continue to debate) whether the purpose and design of the trial really was generating any new findings, the controversy generated by COURAGE is not specific to off label uses and has no direct relation to this NCD topic.

As mentioned, coronary stenting is one of the most studied medical device procedures. This evidence-based approach to these therapies means that there continues to be a steady cadence of publications and presentations related to the safety and outcomes associated with coronary stenting. Fortunately for physicians and others the existing platform of information on off label as well as on label uses is being supplemented by a robust set of emerging data. The medical community has largely interpreted this data as affirming the role of DES in the off label subpopulations. Further information on these findings is included and discussed in this document.

Based on the very substantial consistency of local coverage determinations (LCDs) by CMS’ carriers, FIs and MACs, Medicare contractors view these therapies as the standard of care for many off label procedures. Currently, approximately 20 carrier and 5 FI PCI LCDs exist with a few of those policies converted by MACs for Part A and Part B. All the LCDs include off label coverage indications.

Notably, the volume and mix of coronary stent procedures received by Medicare beneficiaries is relatively stable at this time. As study data emerges physicians will continue to evaluate applicable patient CAD treatments but no dramatic changes are expected in the near term.

In sum, the utilization of BMS and DES in a wide variety of subpopulations are informed by treatment guidelines that are based on a broad and deep set of data which demonstrates the views of key professional societies of the safety, efficacy and reasonableness of this procedure. Finally, the approaches taken by the local contractors bear witness to physicians’ and other stakeholders’ perception of the appropriateness of these therapies in off label patient populations.

The Tables 1, 2 and 3 below are exerts from the ACC/AHA/SCAI guideline Tables 2, 11 and 12. In the right column, we have noted guidelines that correspond with expanded uses which may be interpreted by some as being off-label. Further updating of the practice guidelines is expected as new and relevant data becomes available providing a resource for physicians for applicable patient care.

Table 1 Excerpts from ACC/AHA/SCAI Practice Guidelines Table 2

Table 3 Excerpts from ACC/AHA/SCAI Practice Guidelines Table 12

By way of introduction to the vast array of information surrounding coronary stenting, below are summaries of four studies that have off label subpopulations as part of the analysis, and a brief overview of the FDA Advisory Panel that examined late stent thrombosis. Clearly, there are many more studies that could be examined should a broader and deeper analysis of the role of these subpopulations be pursued. Nonetheless, what follows below is a fairly representative sample of the kinds of evidence that exist for these therapies.

• The Stone-Kirtane meta analysis of more than 180,000 patients found “DES are safe for both on label and off label use, and have comparable efficacy in both RCTs and in the real-world”
  • DES resulted in a highly significant 20% reduction in mortality
  • A significant 11% reduction in MI, and
  • A highly significant 47% reduction in TVR

All analyses were performed independently by Dr. Stone and Kirtane from the Cardiovascular Research Foundation/Columbia University. Statistical models were the Fixed effects (Inverse-Variance weighted) and the Random effects (DerSimonian and Laird). The fixed effects model was considered the primary model if significant heterogeneity was not present; otherwise random effects was considered primary.

When analyzing the 22 RCTs that had patients (on and off label) who were were randomized to either DES or BMS, and followed for >1 yr, those who received DES had a non significant 3% and 6% reduction in mortality and MI respectively with a highly significant 55% reduction in TVR. When analyzing the 30 off label registries in which 174,302 pts were treated with either DES or BMS and followed for >1 yr, DES resulted in a highly significant 20% reduction in mortality, a significant 11% reduction in MI and a highly significant 47% reduction in TVR. The authors concluded that “These findings, derived from more than 180,000 patients treated in 52 studies, strongly suggest that DES are safe for both on label and off label use, and have comparable efficacy in both RCTs and in the real-world” (16-44).

• The ARRIVE 1 and 2 U.S. consecutive enrollment post-market registry (TAXUS® Express2™ Coronary Stent System) capturing more than 7,400 patients (including 64% expanded use) resulted in event rates that remained clinically acceptable through two years
  • ARRIVE’s high percentage of expanded-use cases is similar to other registry populations including DEScover (47% of 5,541 DES patients), EVENT (55% of 3,323 analyzed DES patients) and the National Heart, Lung, and Blood Institute Dynamic Registry (NHLBI, 49% of 2693 DES patients)
  • ARRIVE 1 & 2 real-world TAXUS outcomes compare well to the expected mortality of CABG, the common treatment alternative for the most complex of these patients

The ARRIVE data provides some of the best estimates of DES use for off label indications, which is highly relevant to clinical practice. Expanded use procedures accounted for 64% of procedures in ARRIVE.

The proportion of off label cases in ARRIVE is largely similar to the populations in DEScover (47% of 5,541 DES patients) (48), EVENT (55% of 3,323 analyzed DES patients) (49), the National Heart, Lung, and Blood Institute Dynamic Registry (NHLBI, 49% of 2,693 DES patients) (45), and the American College of Cardiology National Cardiovascular Data Registry for 2003-2004 (21.4% of the over 400,000 DES procedures) (47).

As expected, all of the above studies had some level of increased adverse events given the increased complexity of the patients. For example, in DEScover(48) off label patients receiving DES had significantly higher 1-year rates of death, TVR, and ST , while in EVENT (49) there was more TLR and ST and in the NHLBI (45) there were higher 1-year rates for death, MI, and revascularization. Such differential outcomes have been reported for sirolimus-eluting stent-treated populations as well (50). At the same time, off label use was not always associated with increased risk of adverse outcomes. In NHLBI DES was not associated with increased risk of death or MI, however there was significantly lower risk of TVR.

The increased rate of ST for ARRIVE expanded use patients was concentrated during the first 30 days, a pattern similar to that of complex BMS patients (51). In sum, the expanded-use patients in ARRIVE 1 & 2 reflect the broad spectrum of disease routinely treated in the interventional laboratory and expectedly show higher adverse event rates in the first year. Real-world TAXUS outcomes in ARRIVE 1 & 2 compared well to the expected mortality of CABG, the common treatment alternative for the most complex of these patients.

• The National Heart, Lung and Blood Institute (NHLBI) Dynamic Registry found that:
  • DES outcome of death or MI was at least as safe as the BMS in all instances
  • The risk of repeat revascularization was lower among patients treated with DES than among those treated with BMS for most sub-groups

Results showed DES were used in an off label manner in 59% of patients. Off label versus “on label” use of DES was associated with higher rates of death, myocardial infarction, target vessel revascularization, major adverse cardiac events, and stent thrombosis at nine months and two years which are consistent with the higher risk clinical and lesion profile. However, when compared to the use of BMS in these off label patients and lesions, use of DES had lower rates of death, myocardial infarction, target vessel revascularization, and major adverse cardiac events at nine months and two years and had lower rates of stent thrombosis at nine months. In sum, the authors feel their data supports the use of DES for off label indications in selected patients.

Based on review of these data, the panel concluded that when DES were used for their approved indications (on label) the risk of late DES thrombosis did not outweigh the advantages over BMS in reducing rates of repeat revascularization (10). The panel recognized that with more complex patients, there is an expected increased risk in adverse events in these subsets. The panel generally agreed that off-label use of DES is associated with an increased risk of stent thrombosis, death and MI when compared to on-label use of DES. The panel did not find sufficient data were available to identify subsets of patients at a particularly increased risk.

SYNTAX (SYNergy Between PCI With TAXUS and Cardiac Surgery sponsored by Boston Scientific): SYNTAX is a 1,800-patient, prospective, multicenter, multinational, randomized study with nested registries that enrolled all-comers with de novo 3-vessel disease (3VD) and/or LM disease. The study will define the roles of CABG and PCI using drug-eluting stents in the contemporary management of LM and 3VD (52).

HORIZONS (Harmonizing Outcomes With Revascularization and Stents in Acute Myocardial Infarction sponsored by Cardiovascular Research Foundation, New York): In the HORIZONS-AMI trial, 3,602 patients with AMI undergoing primary PCI were prospectively randomized to either a polymer-based paclitaxel-eluting stent or to an otherwise identical BMS. This study, for which Boston Scientific provided funding, will determine whether paclitaxel-eluting stents safely reduce rates of ischemic target lesion revascularization compared with BMS in the setting of primary PCI (53).

FREEDOM (Future Revascularization Evaluation in Patients With Diabetes Mellitus: Optimal Management of Multivessel Disease sponsored by National Heart, Lung, and Blood Institute (NHLBI)): The FREEDOM Trial is designed to determine whether CABG or percutaneous coronary intervention (PCI) is the superior approach for revascularization of diabetic patients. The FREEDOM Trial is a multicenter, open-label prospective randomized superiority trial of PCI versus CABG in at least 2,000 diabetic patients in whom revascularization is indicated. The FREEDOM Trial is an international study designed to define the optimal revascularization strategy for the diabetic patient with multivessel coronary disease (54).

PROTECT (Patient Related OuTcomes With Endeavor Versus Cypher Stenting Trial sponsored by Medtronic Bakken Research Center): An international randomized controlled trial to estimate rates of Very Late Stent Thrombosis (VLST > 1 year). In this all comer trial 8,800 patients from > 200 sites will be randomized 1:1 to Endeavor or Cypher. The primary endpoint will be ARC defined definite or probable stent thrombosis at 3 years.

XIENCE V USA (XIENCE™ V Everolimus Eluting Coronary Stent System (EECSS) USA Post-Approval Study sponsored by Abbott Vascular): An all comers registry of 5,000 patients across the USA looking at usage patterns and outcomes of real world analysis of the XIENCE V/PROMUS DES.

1. Moses JW, Leon MB, Popma JJ, et al. Sirolimus-eluting stents versus standard stents in patients with stenosis in a native coronary artery. N Engl J Med 2003;349:1315–23.
2. Stone GW, Ellis SG, Cox DA, et al. One-year clinical results with the slow-release, polymer-based, paclitaxel-eluting Taxus stent: the TAXUS-IV trial. Circulation 2004;109:1942–7.
3. Sousa JE, Costa MA, Abizaid A, et al. Four-year angiographic and intravascular ultrasound follow-up of patients treated with sirolimus eluting stents. Circulation 2005;111:2326 –9.
4. Pfisterer M, Brunner-La Rocca HP, Buser PT, et al. Late clinical events after clopidogrel discontinuation may limit the benefit of drug-eluting stents: an observational study of drug-eluting versus bare-metal stents. J Am Coll Cardiol 2006;48:2584 –91.
5. Bavry AA, Kumbhani DJ, Helton TJ, Borek PP, Mood GR, Bhatt DL. Late thrombosis of drug-eluting stents: a meta-analysis of randomized clinical trials. Am J Med 2006;119:1056–61.
6. Lagerqvist B, James SK, Stenestrand U, et al. Long-term outcomes with drug-eluting stents versus bare-metal stents in Sweden. N Engl J Med 2007;356:1009 –19.
7. Eisenstein EL, Anstrom KJ, Kong DF, et al. Clopidogrel use and long-term clinical outcomes after drug-eluting stent implantation. JAMA 2007;297:159–68.
8. Food and Drug Administration. Circulatory System Devices Advisory Panel Transcript for December 8, 2006, Meeting. Available at: http://www.fda.gov/ohrms/dockets/ac/06/transcripts/2006 – 4253t2. rtf. Accessed February 2, 2007.
9. Maisel WH. Unanswered questions— drug-eluting stents and the risk of late thrombosis. N Engl J Med 2007;356:981– 4.
10. Farb A, Boam AB. Stent thrombosis redux—the FDA perspective. N Engl J Med 2007;356:984 –7.
11. D’Agostino RB Jr, D’Agostino RB Sr. Estimating treatment effects using observational data. JAMA 2007;297:314–6
12. Deeks J, Bradburn M, Localio R, Berlin J. Much ado about nothing: meta-analysis for rare events. 6th Cochrane Colloquium, Baltimore, MD, USA, 1998.
13. Sutton A, Cooper N, Lambert P, Jones D, Abrams K, Sweeting M. Meta-analysis of rare and adverse event data. (Abstract). Pharmacoeconomics Outcomes Res 2002;2:367.
14. Lu G, Ades AE. Combination of direct and indirect evidence in mixed treatment comparisons. Stat Med 2004; 23: 3105–24.
15. Stone GW. American College of Cardiology 2008 Oral Presentation. Available http://www.tctmd.com/show.aspx?id=66906
16. TAXUS SR Meta-analysis presented by Ellis, TCT 2007
17. PASSION Laarman, EuroPCR 2007
18. TSEARCH Daemen et al., Eurointervention (2006) 2:330-337
19. Applegate RJ, Sacrinty MT, Kutcher MA, Santos RM, Gandhi SK, Baki TT, Little WC. off label stent therapy 2-year comparison of drug-eluting versus bare-metal stents. J Am Coll Cardiol. 2008;51(6):607-614
20. Williams DO, Abbott JD, Kip KE. Outcomes of 6906 patients undergoing percutaneous coronary intervention in the era of drug-eluting stents: report of the DEScover Registry. Circulation. 2006;114:2154–62.
21. BASKET-(LATE). Pfisterer et al., JACC (2006) 48:2584-91
22. Cypher Meta-analysis. Presented by Leon, TCT 2006
23. Brodie BR ST, Downey W, Humphrey A, et. Al. for the STENT Group. Outcomes and Complications With Off label Use of Drug-Eluting Stents. Results From the STENT (Strategic Transcatheter Evaluation of New Therapies) Group. J Am Coll Cardiol Interv. 2008;1(4):405-414.
24. Washington Hospital Center Experience. Steinberg et al., American Journal of Cardiol. (2007) 99:599-602
25. Marzocchi A, Saia F, Piovaccari G, et al. Long-term safety and efficacy of drug-eluting stents: two-year results of the REAL (REgistro AngiopLastiche dell'Emilia Romagna) multicenter registry. Circulation. 2007;115(25):3181-3188.
26. ONASSIS. Voudris et al., Journal of Invasive Cardiology (2005) 8:401-405
27. Pache et al., European Heart Journal (2005) 26:1262-1268
28. Suttorp MJ, Laarman GJ, Rahel BM, et al. Primary Stenting of Totally Occluded Native Coronary Arteries II (PRISON II): a randomized comparison of bare metal stent implantation with sirolimus-eluting stent implantation for the treatment of total coronary occlusions. Circulation. 2006;114:921– 8.
29. Sabate M, Jimenez-Quevedo P, Angiolillo DJ, et al. Randomized comparison of sirolimus-eluting stent versus standard stent for percutaneous coronary revascularization in diabetic patients: the diabetes and sirolimus-eluting stent (DIABETES) trial. Circulation. 2005;112:2175–83.
30. SCANDSTENT. Kelbaek et al., JACC (2006) 47(2):449-59
31. TYPHOON. Spaulding et al., NEJM (2006) 355:1093-104
32. SESAMI. Kastrati et al., NEJM (2007) 356:1030-9
33. SCAAR. Presented by James, ESC 2007
34. Western Denmark. Presented by Jensen, TCT 2007
35. SES Smart. Ardissino et al., JAMA (2004) 292(22):2727-34
36. MISSION. Presented by van der Hoeven BL, AHA 2006
37. Ortolani et al., Catheter Cardiovasc Interv (2007) 69:790-98
38. Tu JV, Bowen J, Chiu M, et. Al. Effectiveness and safety of drug-eluting stents in Ontario. N Engl J Med. 2007;357(14):1393-1402.
39. Acuity. Presented by Mehran ESC 2007
40. NY State presented by Hannan, TCT 2007
41. ASAN. Presented by Park TCT 2007
42. GHOST. Presented by Harjai, TCT 2007
43. MIDAS. Presented by Vagonescu, TCT 2007
44. MASSACHUSETTS. Presented by Mauri, AHA 2007
45. Marroquin OC, Selzer F, Mulukutla SR,et al. A comparison of bare-metal and drug-eluting stents for off label indications. N Engl J Med. 2008;358(4):342-352.
46. Galloe AM, Thuesen L, Kelbaek H, et. Al. Comparison of paclitaxel-and sirolimuseluting stents in everyday clinical practice: the SORT OUT II randomized trial. JAMA. 2008;299(4):409-416.
47. Rao SV, Shaw RE, Brindis RG, et. Al. On-versus off label use of drug-eluting coronary stents in clinical prac (report from the American College of Cardiology National Cardiovascular Data Registry [NCDR]). Am J Cardiol. 2006;97(10):14781481.
48. 48.Beohar N, Davidson CJ, Kip KE, et al. Outcomes and complications associated with off label and untested use of drug-eluting stents. JAMA. 2007;297(18):19922000.
49. Win HK, Caldera AE, Maresh K, Lopez J, Rihal CS, Parikh MA, Granada JF, Marulkar S, Nassif D, Cohen DJ, Kleiman NS. Clinical outcomes and stent thrombosis following off label use of drug-eluting stents. JAMA. 2007;297(18):20012009.
50. Jeremias A, Ruisi CP, Kirtane AJ, Lee T, Sylvia B, Pinto DS, Ho KK, Cutlip DE, Carrozza JP, Jr., Cohen DJ. Differential outcomes after sirolimus-eluting stent implantation: comparing on label versus off label patients in the 'real world'. Coron Artery Dis. 2008;19(2):111-115.
51. Honda Y, Fitzgerald PJ. Stent thrombosis: an issue revisited in a changing world. Circulation. 2003;108(1):2-5.
52. Ong AT, Serruys PW, Mohr FW, et. al. Am Heart J 2006;151:1194-204.
53. Mehran, R, Brodie, B, Cox, DA, et al. Am Heart J 2008;156:44-56.
54. Farkouh ME,, Dangas G, Leon MB, et al. Am Heart J 2008;155:215-23.
55. Stone GW, Moses JW, Ellis SG, et al. Safety and efficacy of sirolimus and paclitaxeleluting coronary stents. N Engl J Med. 2007;356:998–1008.
56. Spaulding C, Daemen J, Boersma E, Cutlip DE, Serruys PW. A pooled analysis of data comparing sirolimus-eluting stents with bare-metal stents. N Engl J Med. 2007;356:989 –97.
57. Kastrati A, Mehilli J, Pache J, et al. Analysis of 14 trials comparing sirolimus-eluting stents with bare-metal stents. N Engl J Med. 2007;356: 1030–9.
58. King SB III, Smith SC Jr, Hirshfeld JW Jr, Jacobs AK, Morrison DA, Williams DO. 2007 focused update of the ACC/AHA/SCAI 2005 Guideline Update for Percutaneous Coronary Intervention: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines: (2007 Writing Group to Review New Evidence and Update the 2005 ACC/AHA/SCAI Guideline Update for Percutaneous Coronary Intervention). Circulation. 2008;117:261–295.
59. Stefan James MD. Oral Presentation ESC 2007. available http://www.crtonline.org/flash.aspx?PAGE_ID=4647
60. Boden WE, O’Rourke RA, Teo KK, et al. Optimal medical therapy with or without PCI for stable coronary disease. N Engl J Med 2007;35:1503–16.
61. .Keeley EC, Boura JA, Grines CL. Primary angioplasty versus intravenous thrombolytic therapy for acute myocardial infarction: a quantitative review of 23 randomised trials. Lancet 2003;361:13–20.
62. Mehta SR, Cannon CP, Fox KAA, et al. Routine vs. selective invasive strategies in patients with acute coronary syndromes—a collaborative meta-analysis of randomized trials. JAMA 2005;293:2908 –17.
63. Bavry AA, Kumbhani DJ, Rassi AN, et al. Benefit of early invasive therapy in acute coronary syndromes—a meta-analysis of contemporary randomized clinical trials. J Am Coll Cardiol 2006;48:1319 –25.
64. Henderson RA, Pocock SJ, Clayton TC, et al. Seven-year outcome in the RITA-2 trial: coronary angioplasty versus medical therapy. J Am Coll Cardiol 2003;42:1161– 70.
65. Parisi AF, Folland ED, Hartigan P, Veterans Affairs ACME Investigators.A comparison of angioplasty with medical therapy in the treatment of single-vessel coronary artery disease. Veterans Affairs ACME Investigators. N Engl J Med 1992;326:10–6.
66. Hueb WA, Bellotti G, deOliveira SA, et al. The Medicine, Angioplasty or Surgery Study (MASS): a prospective, randomized trial of medical therapy, balloon angioplasty or bypass surgery for single proximal left anterior descending artery stenoses. J Am Coll Cardiol 1995;26:1600 –5.
67. Pitt B, Waters D, Brown WV, et al. Aggressive lipid-lowering therapy compared with angioplasty in stable coronary artery disease. N Engl J Med 1999;341:70–6.
68. Hueb W, Lopes NH, Gersh BJ, et al. Five-year follow-up of the Medicine, Angioplasty, or Surgery Study (MASS II)—a randomized controlled clinical trial of 3 therapeutic strategies for multivessel coronary artery disease. Circulation 2007;115:1082–9.
69. Katritsis DG, Ioannidis JPA. Percutaneous coronary intervention versus conservative therapy in nonacute coronary artery disease—a meta-analysis. Circulation 2005;111:2906 –12.
70. Smith SC Jr., Feldman TE, Hirshfeld JW Jr., et al. ACC/AHA/SCAI 2005 guideline update for percutaneous coronary intervention: report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (ACC/AHA/SCAI Writing Committee to Update the 2001 Guidelines for Percutaneous Coronary Intervention). J Am Coll Cardiol. 2006;47:e1–121.
71. Mehta HR et al. Circulation 2005;112:II-793.
72. Hannan EL, Racz M, Holmes DR, et al. Impact of completeness of percutaneous coronary intervention revascularization on long-term outcomes in the stent era. Circulation 2006;113:2406 –12.
73. Pfisterer M, Brunner-La Rocca HB, Buser PT, et al. Late clinical events after clopidogrel discontinuation may limit the benefit of drug-eluting stents: an observational study of drug-eluting stents versus bare-metal stents. J Am Coll Cardiol 2006;48:2584-91.
74. Nordmann AJ, Briel M, Bucher HC. Mortality in randomized controlled trials comparing drug-eluting vs. bare metal stents in coronary artery disease: a metaanalysis. Eur Heart J 2006;27:2784-814.
75. Camenzind E, Steg G, Wijns W. Safety of drug-eluting stents: a meta-analysis of 1st generation DES programs. Presented at the European Society of Cardiology 2006 World Congress, Barcelona, September 2–6, 2006.
76. Weintraub, William S. NEJM, Effect of PCI on Quality of Life in Patients with Stable Coronary Disease; Aug 14, 2008 vol. 359 no. 7 pages 677-687
77. Rosamond, Wayne etc er al; Circulation, American Heart Association; 2008;117.
78. Caldwell DM, Ades AE, Higgins JP. Simultaneous comparison of multiple treatments: combining direct and indirect evidence. BMJ 2005; 331: 897–900.

In answer to CMS’ question on whether there is evidence to specify groups of patients that do and do not benefit from angioplasty and stenting in the peripheral vascular system, we can respond that endovascular procedures are beneficial for the patient groups defined by criteria specified in the Trans-Atlantic Inter-Society Consensus guidelines (TASC and TASC-II), the American College of Cardiology/American Heart Association (ACC/AHA) 2005 Practice Guidelines for the Management of Patients with Peripheral Arterial Disease (referred to as the ACC/AHA guidelines), and available literature. We cannot affirm that there are groups that do not benefit from endovascular procedures.

The peripheral vascular system is highly individualized, with numerous vessels possessing their own morphology. The variety of treatment strategies for peripheral artery disease (PAD) is necessitated by the highly individualized nature of the disease and the variable morphology of the peripheral vessels. Thus, it is critical to maintain access to the entire spectrum of clinical choices for all patients.

In our comments below, Boston Scientific provides greater detail on both the landscape for PAD and the unique clinical characteristics that define and evidence related to treatment outcomes associated with this condition. We also provide a detailed list of 27 ongoing studies in Appendix 1 of this document, indicating that there will be substantial additional data available in the next several years to further define optimal management of PAD. Based on our assessment of the PAD landscape, the need to preserve individualized treatment given the peripheral arteries’ widely varying morphology, and consistency of current treatment standards, Boston Scientific believes CMS should maintain local coverage practices and place a low priority on initiating an NCD for peripheral interventions.

PAD is a condition that affects eight to ten million Americans and up to 20% of people age 65 or older.^1,2 Atherosclerosis is the most common cause of chronic limb ischemia although other factors may be present. Risk factors for PAD are essentially the same as for coronary artery disease (CAD) with cigarette smoking and diabetes playing a more prominent role. Patients with renal insufficiency also have a high prevalence of PAD.³

PAD can present in a variety of forms, from asymptomatic to intermittent claudication or critical ischemia (rest pain and/or tissue loss). Even asymptomatic patients experience a significant impairment in lower extremity function and a decrease in quality of life over time.^4,5 The estimated mortality rate for patients with claudication is 30% at five years increasing to 70% for patients with critical limb ischemia.⁶

In general, the degree of PAD reflects the severity of systemic atherosclerosis. Survival is inversely proportional to the severity of the ischemia at presentation.⁷ Not all vascular sectors in the lower limbs have the same impact on morbidity and mortality. Some studies show that arterial obstructions below the knee are predictors of worse survival rates when compared with other vascular areas.⁸ Complex or multilevel obstructions at the iliac level usually only cause symptoms of claudication, but when located in the femoral or distal vessels, these obstructions pose a risk of limb loss, causing rest pain and/or necrosis.

Importantly, due to the consistency in recommendations across both sets of guidelines, there have not been significant questions raised about the treatment for PAD or the role of the various therapies that have become the standard of care. TASC II and ACC/AHA guidelines have been incorporated into all endovascular training programs in the United States and also into local Medicare coverage policies, creating a consistent foundation for the delivery of care and for fairly uniform coverage throughout the country.

Given specialty society consensus and the ongoing review of relevant clinical literature, it is clear that while there is some variance in approaches by individual physicians, the TASC recommendations are well-followed and that significant questions or controversies have not emerged about treatment for PAD. Rather, specialty society guidelines and literature recommend well-followed treatment paradigms that allow for the unique characteristics of each patient and each lesion while at the same time detailing an appropriate cascade of therapies.^9,10 Over the next several years, additional data from over 20 studies will be available to further hone these guidelines and the definition of optimal therapy for PAD (studies are listed in Appendix 1).

Also reflecting the standardization of treatment approaches is the fact that there is strong general consistency across Medicare local coverage policies for peripheral interventions and that these policies reflect adherence to the recommendations of the TASC II and ACC/AHA guidelines (see Table below).

The Trans-Atlantic Inter-Society (TASC) Working Group started in 1996 as a means to achieve an international consensus across different clinical and research societies to provide guidelines for the treatment of PAD. The guidelines were first published in 2000 (TASC) and were revised in 2007 (TASC II). In this latest revision, the consensus document had a broader international representation, with sixteen cooperating societies representing seven specialties:

• Cardiology;
• Podiatry;
• Vascular Surgery;
• Diabetes Care;
• Interventional Radiology;
• Angiology; and
• Vascular Medicine and Biology.¹¹

TASC II reflects the previously mentioned complexity of lesions by dividing the treatment recommendations into different sections (supra-inguinal or aorto-iliac disease and infrainguinal disease, the latter subdivided into femoro-popliteal and infrapopliteal).

Suprainguinal (Aortoiliac) Disease
For the iliac arteries, the nature of the arteries themselves, excellent technical and clinical results and the low complication rate of this therapeutic method have made iliac angioplasty and stenting the standard of care in this vascular bed. This includes the most complex lesions when surgery would be indicated but the co-morbidities of the patients would put them at a higher risk for complications.¹²

The iliac arteries are fairly elastic and straight and do not bear high compression forces, making them a “grateful” area to work in and amenable to easy endovascular repair. This situation differs with the open surgical scenario where gaining access to the arteries may be difficult due to their deep location and where severe complications may arise, such as bowel perforation or iliac vein injury, which is potentially catastrophic.

Multiple papers have been published in peer-reviewed journals with long series of patients across the world, all of them drawing very similar conclusions for iliac angioplasty and stenting. Technical success is close to 100%, and more than 80% of the treated segments remain free of revascularization procedures at 5 years.¹³ Several randomized studies assess the efficacy of angioplasty and stenting in the iliac territory, the most important ones being the Dutch Iliac Stent Trial and the CRISP-US trial. The former indicates that endovascular treatment of the iliac arteries yields very good results even at long term follow up (median of 5-8 years) no matter what technique is used, either primary stenting or angioplasty with selective stenting.¹⁴ These impressive results were reached even though this study was performed during the nineties, when a wide variety of angioplasty balloons and more current stent materials were not available. The CRISP-US trial, published in 2004, affirmed these by comparing two self-expanding stents made of different materials. While the results did not prove any statistical difference in restenosis among different materials, they confirmed the trend of extraordinary technical and clinical success. The primary endpoint of this trial was a composite of restenosis at 9 months, target vessel revascularization at 9 months and 30day mortality. Ninety to ninety-five percent of patients were free of restenosis and did not need a second intervention during 9 months. At 12 months, the primary patency rate was 95%, confirming the outstanding results of angioplasty and stenting in this vascular area. ¹⁵ Many large case series support these findings, and some advocate the use of the aforementioned endovascular procedures to treat the most complex lesions, using primary stenting as the preferred method. ^16,17,18

In addition to the published data supporting iliac stenting, peri-operative morbidity and hospital length of stay are typically significantly lower for stenting compared with surgery. As a result, some physicians have the opinion that the post-operative period after iliac stenting is a matter of hours with minimal anesthesia requirements (local anesthesia at the puncture site), virtual absence of pain and therefore little need for pain medication, and same-day hospital discharge allowing the patient to return to normal activity within 24 hours of the intervention.

Infrainguinal Disease

1. Superficial Femoral Artery (SFA)
The SFA is certainly the most challenging vessel with respect to results after either endovascular treatment of any modality or bypass surgery. The SFA has very particular characteristics: it is the longest non-segmented artery in the human body; it is situated between two major articulations (the hip and the knee) and it runs along very powerful groups of muscles. This environment makes this artery subject to high forces during normal physical activity. Walking, running, standing from a sitting position and stair climbing are movements that cause flexion, extension, compression and torsion of the SFA. To be able to resist these mechanical forces, the vessel wall cannot have the same configuration as other arteries in the body. The SFA has a stronger muscular component as compared with the more elastic configuration of the iliac arteries. This is useful to avoid collapsing when movement-related pressures are exerted on the artery, particularly at the Hunter’s canal, in the distal part of the thigh, where the SFA goes through a major muscle group.

Those anatomical peculiarities have repercussions for interventions. Primary angioplasty without stenting in this territory, particularly in long lesions, has very high short-term technical success with a low rate of complications, but when mid and long-term data are analyzed, the results are not as promising.¹⁹ Several case-series studies report poor outcomes for balloon angioplasty alone at long term follow-up, especially for long lesions (>10 cm). The primary patency rates at 1 year average 40%.^20,21,22

Similar results apply for surgery; due to anatomical considerations, bypasses are long and sometimes must be performed using synthetic materials. The previously-mentioned anatomical characteristics result in poor outcomes for surgery as well^23,24.Although the results of endovascular and open interventions in the SFA are not comparable to those obtained in other vascular territories, patients must be treated aggressively when medical therapy has failed or is unable to control the progression of the disease.

Even in the most complicated situations, open surgery is not always the answer. As shown in the BASIL trial (Bypass versus Angioplasty in Severe Ischaemia of the Leg), a multicenter randomized trial published in Lancet in 2005, surgery did not provide any benefit over angioplasty in terms of amputation-free survival at 2 years.²⁵ Given the potential complications and comorbidities associated with any open surgery, currently available minimally invasive technology may offer physicians an attractive long term risk/benefit ratio in the subset of patients with severe SFA disease and an overall worsened cardio-vascular condition.

With the advent of stents, the results for endovascular interventions in the SFA were expected to be improved, but several multicenter randomized studies comparing primary stenting to balloon angioplasty failed to prove that hypothesis ^26,27,28,29. The conclusions suggested that stents should be used in the SFA only in selected occasions when a technical failure was present after balloon angioplasty.³⁰ It should be noted that these studies were conducted in patients with short lesions (~ 2 cm), where primary angioplasty has shown excellent results, and they used balloon-expandable stainless-steel stents. The recent FAST (Femoral Artery Stenting Trial) confirmed earlier findings that primary stenting is still not justified in short lesions (< 5 cm) due to the efficacy of simple PTA (Percutaneous Transluminal Angioplasty) and advocates the use of stents only for selected cases. ³¹

The development of nitinol stents changed the panorama of long lesion treatment. As opposed to balloon-expandable stents, nitinol stents have the capability of regaining the original lumen or re-adapting after external compression, a characteristic that has demonstrated benefits in this territory. Several trials sought to assess the efficacy of nitinol stents in order to change the original recommendations on SFA stenting. The results showed an improvement in long term patency over balloon-expandable stents.^32,33,34,35 Accordingly, for long lesions in the SFA, primary stenting with a nitinol stent has become highly advisable over plain balloon angioplasty. The results for primary stenting in long SFA lesions using nitinol stents are very good, showing a primary patency rate of nearly 80% at 2 years and a 90% assisted primary patency rate at 5 years in some reports.³⁶

Differences with respect to material resistance and subsequent fracture rate of stents placed in the SFA are recent and permanent topics in the management of PAD in the SFA. The clinical impact of these issues is being studied, showing a tendency to higher risk of restenosis and stent occlusion when fractures occur, although not all types of fractures have demonstrated clinical repercussions.^37,38,39,40

Despite remaining questions that are in the midst of being answered through ongoing studies, the results of minimally invasive therapies have dramatically improved over the last decade. The current TASC II recommendations have been broadened for endovascular treatment of femoropopliteal lesions. Endovascular procedures (PTA alone or PTA plus stenting) are the treatments of choice in single stenoses < 10 cm and in single occlusions < 5 cm. PTA alone or PTA plus stenting are also the preferred treatments in single or tandem lesions up to 15 cm in length. On longer lesions (> 15 cm) surgery is recommended, although when patient risk factors for surgery are considered, angioplasty and stenting have remained the therapeutic choice in some cases.⁴¹

Little is known about why the results of either endovascular procedures or open surgery in this area differ from the ones obtained with very similar therapies in the iliac arteries or in the coronary circulation. The length of the vessel, the diffuse disease and the low flow rates in the SFA could offer some possible explanations. Patients with infrainguinal disease also tend to have a lower ankle-brachial index (ABI) than patients with aortoiliac disease; the lower this parameter is, the worse the prognosis becomes.⁴² Medical comorbidities such as diabetes may influence the outcomes of endovascular interventions.⁴³ The excessive twisting and bending of the SFA also plays a key role on restenosis after treatment. Experimental studies in animals have shown that the more distal the arteries are, the less successful their remodeling is and also that biomechanical forces are a trigger of neointimal hyperplasia leading to restenosis.^44,45 Other factors such as the type of lesion and the runoff (number of patent arteries distal to the lesion) have shown to be major determinants of the outcomes.⁴⁶

2. Infrapopliteal Arteries
Surgical bypass and endovascular procedures below the popliteal artery are generally limited to the treatment of CLI (Critical Limb Ischemia). There are no data available that allow us to compare endovascular procedures to bypass surgery in this region for the treatment of intermittent claudication. However, current TASC II guidelines for this vascular area acknowledge the increasing evidence supporting the use of PTA when continuous flow to the foot can be achieved, especially in patients with medical comorbidities.⁴⁷ Technical success is close to 90% in most series and limb salvage at 1 year is over 80%.⁴⁸ As discussed previously, patients with CLI and infrapopliteal disease have decreased survival rates and this is a reflection of an advanced and generalized atherosclerotic status.⁴⁹ This situation puts patients at high risk for major surgical interventions; minimally invasive therapies have typically provided very good technical results with an extraordinary limb salvage rate and low procedure-related morbidity and mortality.⁵⁰ Moreover, PTA has not generally precluded subsequent endovascular procedures or even surgical bypass if needed.

A clear example of evolution of treatment recommendations associated with PAD is the ongoing revision of the TASC guidelines. In seven years (TASC 2000 – TASC II 2007), not only the classification of the lesions but also the recommended therapeutic approaches for different types of lesions have significantly changed.^51,52 In the latest TASC guidelines (TASC II), minimally invasive procedures continue to be recognized as a therapeutic alternative that can provide certain patients with a prompt symptom relief, expedited recovery and a low rate of complications. The TASC and the ACC/AHA guidelines are likely to evolve further as additional data from the numerous ongoing studies of PAD therapies (listed in Appendix 1) become available.

The unique nature of PAD necessitates patient-specific treatment strategies that do not lend themselves to a wholesale “one size fits all” approach to treatment or coverage. TASC II guidelines address the differences in management of PAD in distinct vascular beds, and these guidelines are well-accepted and have been incorporated into clinical practice. Moreover, current local coverage policies are entirely appropriate and largely consistent, reflecting widely-accepted and adopted practice guidelines.

Therefore, Boston Scientific believes that CMS should assign low priority to opening an NCD for peripheral vascular procedures.

We appreciate CMS’ inquiry into whether the evidence is adequate to demonstrate health benefits in patients treated with cardiac ablation. Over the past 10 years, catheter ablation for patients with Atrial Fibrillation (AF) who do not respond to pharmacological therapy has “evolved rapidly from a highly experimental unproven procedure, to its current status as a commonly performed ablation procedure performed in many major hospitals throughout the world.”⁵³ As CMS evaluates whether to establish an NCD in the area of AF ablation, Boston Scientific would like to review and discuss the published evidence as well as review trials currently underway.

Initially, AF ablations were more commonly performed on the AV node for ventricular rate control.⁵⁴ Success of the surgical Maze III procedure in the 1990s led to the transvenous approach of linear RF catheter lesions in the right atrium.⁵⁵ The consensus now is that “ablation strategies which target the pulmonary veins (PV) and/or PV antrum are the cornerstone for most AF ablation procedures.”⁵⁶ Existing clinical evidence supporting these strategies consists of both non-randomized and randomized, single-and muti-center trials. Please see Tables 1A and 1B below for a summary of these studies and their outcomes. Clinical acceptance of this therapy within the medical community has been built on this evidence, and on the 2006 American and European guidelines for managing patients with Atrial Fibrillation, and more specifically for ablations, the 2007 global expert consensus in this area issued: “HRS/EHRA/ECAS Expert Consensus Statement on Catheter and Surgical Ablation of Atrial Fibrillation: Recommendations for Personnel, Policy, Procedures and Follow Up.”

In addition to the current literature, a number of investigations, including many large-scale, randomized, multi-center clinical trials utilizing radiofrequency, open-irrigated radiofrequency and cryo ablation therapy (point ablation and balloon applications), are ongoing and yet to be completed. A number of these investigations are scheduled to conclude in 2009 or later. An overview of these ongoing clinical trials is provided in Table 2.

As CMS continues to evaluate whether to pursue an NCD for AF procedures, we are available for consultation or can provide further information regarding the existing literature and current practice.