On March 17, 2005, the Centers for Medicare & Medicaid Services (CMS) issued a national coverage determination (NCD) announcing that it was expanding coverage of carotid artery stenting (CAS) for patients at high risk for carotid endarterectomy (CEA) with symptomatic narrowing of the carotid artery of 70% or more. Under this NCD, Medicare also covered patients who met the Food and Drug Administration (FDA)-labeled criteria for carotid stents (ie, patients at high risk for CEA with a symptomatic carotid artery stenosis between 50% and 70% or with an asymptomatic carotid artery stenosis of 80% or more) enrolled in investigational device exemption (IDE) clinical trials, as a routine cost under the clinical trials policy, or enrolled in postapproval studies (PAS). The impact of the 2005 NCD on CAS outcomes across the spectrum of IDE trials, both in high-risk and standard-risk subjects, as well as in FDA-mandated PAS, has been significant.

CMS: THE AFFECT OF THE 2005 NCD

In order to become accredited and seek reimbursement, Medicare required facilities to meet certain minimum standards in performing CAS. These standards included physician training, facility support requirements, as well as data collection to evaluate outcomes in the future. Facilities can obtain accreditation after providing a written affidavit to CMS attesting that the facility had met the standards laid out by CMS.

The expansion of coverage by CMS to FDA-mandated PAS has been a driving force that facilitated and even enabled enrollment in these studies. For every stent system approved, the FDA required sponsors to conduct a PAS with data collection and to submit annual reports to the agency to assess the adequacy of training as well as to uncover any unanticipated or rare event not identified in the pivotal trials. By the end of 2005, CAPTURE, the first of these PAS, had enrolled and analyzed close to 3,000 subjects, while the other two active PAS, EXACT and CASES-PMS, contributed another 600 subjects to the pool in 2005 alone. In parallel (with some overlap) more than 7,000 CAS procedures were reimbursed by CMS by the end of 2005.

By the end of 2009, the year that the last high-risk IDE was initiated, the combined enrollment of all PAS totaled more than 26,000 subjects, while the total number of CAS procedures reimbursed by CMS reached approximately 43,000. The magnitude of CMS's impact can be measured from another perspective: by the end of 2005, within 9 months of the NCD, 768 sites had been accredited by CMS to perform CAS; this number increased by 50% to 1,087 sites by the end of 2009.1

IMPORTANCE AND IMPACT OF THE CMS DECISION

The importance and impact of the CMS decision is evident in the improvement in outcomes observed in the PAS that used the same stent system and embolic protection device (EPD). Between 2004 and 2010, outcomes from CAPTURE (N = 4,225) and CAPTURE-2 (N = 6,079) showed a decline in death and stroke rates, both in symptomatic and asymptomatic patients.2,3 In the symptomatic subgroup, rates decreased from 10.6% to 6.2%, similar to the decrease observed in asymptomatic patients from 5.7% to 3.0%. Analyzing the same single-stent system from the CHOICE PAS (which enrolled an additional 6,000 patients in the Acculink carotid stent/Accunet EPD (Abbott Vascular, Santa Clara, CA) cohort between 2006 and 2011) shows that outcomes continue to trend down with death and stroke rates of 5.1% and 2.8% for symptomatic and asymptomatic groups, respectively (Figure 1).4 Because the stent and EPD had remained unchanged, the patient demographics were similar, and sites overlapped for the most part across the three PAS, the most plausible explanation for these improvements resides in the presence of a learning curve.

LEARNING CURVE

An indirect and remarkable effect of the learning curve was brought to light during the January 26, 2011 Circulatory System Devices Advisory Panel. The panel was gathered by the FDA to review and discuss the results of the Carotid Revascularization Endarterectomy versus Stent Trial (CREST), a physician-sponsored, NIH and industrycofunded randomized clinical trial (RCT). CREST was designed to demonstrate the safety and efficacy of CAS in symptomatic and asymptomatic patients at standard risk for surgery. Although CAS successfully met all of the prespecified hypotheses of noninferiority to CEA, an amazing trend emerged from the analysis of the symptomatic cohort whose enrollment spanned over the entire course of the trial, from 2000 to 2008. After an initial increase in death and stroke rates from 4.4% in 2000 to 2004 to 7.0% in 2005, there was a steady and yearly decline thereafter to 1.8% in 2008.5 In view of all the evidence presented, the panel overwhelmingly voted in favor of the risk-benefit profile of CAS, and on May 6, 2011, the FDA expanded the indication to use of the Acculink stent system in standard-surgical-risk patients.

It seems natural that a learning curve would be present in a very large clinical trial for a new therapy that ran for 8 years. However, the average enrollment in CREST was only six subjects per CAS operator, not enough to provide a learning platform in and of itself.

The follow-up questions for specialists in the field were: Where did the operators learn to perfect their skills, and how did they select more suitable patients for CAS within the RCT framework of the fixed inclusion/exclusion criteria?

The answer is twofold. The FDA-mandated CMS-covered PAS and the exponential growth of CAS literature published since 2000 both played a complementary role. PAS provided formal training in addition to tens of thousands of cases, while operators could continue to learn via peer-reviewed articles, presentations, and live cases at major medical conferences.

FDA: THE TWO WAVES OF IDE CLINICAL TRIALS

At the time of the 2005 NCD, Abbott Vascular (then Guidant) was the only company with an FDAapproved carotid stent, the Acculink stent system, and an ongoing postapproval study (CAPTURE). After this first carotid stent approval in August 2004, six new stent systems were approved by the FDA between 2005 and 2007 (Table 1). This first wave of IDE trials enrolled between 2000 and 2004, and led to stent approval as well as to 510(k) clearance of their corresponding EPDs.

It is important to note that the first wave of IDE clinical trials carried key similarities in trial design, such as patient inclusions/exclusions, primary composite endpoint (30-day periprocedural death, stroke, and myocardial infarction), pre-, post-, and 30-day independent neurological assessment, and independent central adjudication of neurological events. Subsequently, baseline demographics were similar across studies. Not surprisingly, 30-day death and stroke rates were clustered, ranging from 4.0% to 6.9%, with a weighted average of 5.3% (95% CI, 4.6, 6.2%).

New EPDs seeking 510(k) clearance led to a second wave of IDE trials, with enrollment spanning between 2006 and 2010 (Table 2). Like the first wave of IDE trials, these studies included similar patient demographics and were assessed the same way as the first wave of IDE trials. Rates of 30-day death and stroke were also clustered, ranging from 1.8% to 3.6% with a weighted average of 2.6% (95% CI, 1.9, 3.7%).

Several observations can be made in comparing the first wave to the second wave of IDE trials. The enrollment periods do not overlap and are separated by a gap of 2 years (2000 to 2004 for the first wave, and 2006 to 2010 for the second wave). Importantly, outcome rates were halved, from an average of 5.3% to an average of 2.6%, a statistically significant difference of 2.7% (95% CI, 1.3, 3.9%; Fisher's exact test; P < .0001.)

Although improvement in EPD technology used in the second wave, such as proximal protection or better distal protection devices, may have played a role in the observed improvement in outcomes, when these IDE observations are considered along with the aforementioned outcome improvements on a single-stent system and EPD (Acculink and Accunet), the impact of CMS's national coverage decision for FDA-mandated PAS cannot be underestimated.

CONCLUSION

The medical device industry and venture capitalists invest large portions of their funds to create new therapies. The capital is used to demonstrate the safety and efficacy of devices to the FDA and to bring them to market. The products will then take years in the hands of trained practitioners who must overcome learning curves and translate new technologies into superior outcomes. From what we have seen, national coverage decisions by CMS, even if limited in scope, can play a critical role in creating the environment in which these improvements will take place. In addition, the expansion of FDA indications and CMS coverage decisions enable industry reinvestment in better technologies that ultimately benefit patient outcomes.

Patrick Verta, MS Stat, MD, is a freelance consultant in clinical and medical affairs. He has disclosed that he is a shareholder of Abbott Laboratories and Boston Scientific. Dr. Verta may be reached at (714) 202-0993; patrickverta@gmail.com.

  1. Carotid Artery Stenting Facilities. The following facilities have met the CMS's minimum facility standards for performing carotid artery stenting for high risk patients. Available at: http://www.cms.gov/Medicare/Medicare-General-Information/MedicareApprovedFacilitie/ Carotid-Artery-Stenting-Facilities.html. Accessed August 18, 2013.
  2. Gray WA, Yadav JS, Verta P, et al. The CAPTURE registry: results of carotid stenting with embolic protection in the post approval setting. Catheter Cardiovasc Interv. 2007;69:341-348.
  3. Gray WA, Rosenfield KA, Jaff MR, et al; CAPTURE 2 Investigators and Executive Committee. Influence of site and operator characteristics on carotid artery stent outcomes: analysis of the CAPTURE 2 (Carotid ACCULINK/ACCUNET Post Approval Trial to Uncover Rare Events) clinical study. JACC Cardiovasc Interv. 2011;4:235-246. doi: 10.1016/j.jcin.2010.10.009.
  4. Gray WA, Verta P. The Impact of Regulatory Approval and Medicare Coverage on Outcomes of Carotid Stenting. Submitted for publication. 2013 July. In review.
  5. Gray WA, Simonton CA, Verta P. Overview of the 2011 Food and Drug Administration Circulatory System Devices Panel meeting on the ACCULINK and ACCUNET Carotid Artery Stent System. Circulation. 2012;125:2256-2264.