June 29, 2009 Charlene Frizzera Acting Administrator Centers for Medicare & Medicaid Services Department of Health & Human Services Attention: CMS-1406-P P.O. Box 8011 Baltimore, MD 1850 Dear Ms. Frizzera: On behalf of the American College of Gastroenterology (ACG), the American Gastroenterological Association (AGA), and the American Society for Gastrointestinal Endoscopy (ASGE), representing over 16,000 physicians specializing in digestive diseases, we are pleased to provide these comments with respect to CMS’ proposed rule, CMS-1406-P, published on May 22, 2009 in the Federal Register, regarding the proposed addition of Clostridium difficile to the list of possible new quality measures for the FY 2012 payment determination and subsequent years.

INTRODUCTION One of the significant clinical issues impacting gastroenterologists and other health care professionals over the last three to four decades has been nosocomial infections affecting the gastrointestinal tract, such as Clostridium difficile associated diarrhea (CDAD). Many of our educational conferences have focused on CDAD. Our societies have developed patient materials and clinical guidelines, for example Fekerty, R et al. “Guidelines for the Diagnosis and Management of Clostridium Difficile-Associated Diarrhea and Colitis,” (Am. J. Gastroenterol, 92:5, 1997, 739-750), and numerous CDAD articles have appeared in our respective journals. It is through this prism that we approach the proposed rule. CDAD has been and continues to be a serious and challenging problem in clinical gastroenterology. CDAD has been described in the medical literature since the late 1970s. Infectious spores of Clostridium difficile can contaminate the nursing home or hospital environment or non-healthcare settings and, when ingested, bind to the colonic epithelium and cause toxin-mediated cell destruction. Despite significant improvements in diagnosis, effective treatment and infection control programs, outbreaks have continued to occur. Indeed, the rate of severe outbreaks has increased significantly in hospitals in the United States, Canada and Europe. 1 2

1 McFarland, LV, “Update on the Changing Epidemiology of Clostridium Difficile-Associated Disease.” Nature Clinical Practice Gastroenterology & Hepatology, January 2008, Vol., 5, No. 1, 40-48.

In the recent decision to exclude CDAD from the list of hospital-acquired conditions (HAC) published August 19, 2008 in the Federal Register, CMS notes that it would “continue to consult with the CDC [Centers for Disease Control] regarding evidence-based prevention guidelines and coding for CDAD” and “[i]f the evidence warrants, we may consider proposing CDAD as an HAC in the future.” CMS made the same decision in 2007 when it noted in its final rule that while Clostridium difficile is a serious threat to the public health there is not “currently a strategy for reasonably preventing these infections.”

STATUTORY UNDERPINNINGS AND IMPORTANCE The Deficit Reduction Act (DRA) of 2005 (P.L. 109-171) requires the CMS to deny assignment of a case to a higher DRG based on the occurrence of one of the selected hospital-acquired conditions, if that condition was acquired during the hospitalization. It is our understanding that the agency determines whether a condition was acquired during the hospital stay by requiring hospitals to submit data on their claims for payment indicating whether diagnoses were present on admission. The DRA requires the agency to select conditions that are: 1. High cost, high volume, or both 2. Assigned to a higher paying DRG when present as a secondary diagnosis 3. Reasonably preventable through the application of evidence-based guidelines. As will be explained in greater detail below, the debate over these criteria is focused on #3. Our societies agree that CDAD meets criteria #1 and #2. However, we believe that while the incidence of CDAD could be reduced through the application of evidence-based guidelines, the current medical evidence indicates that denying payment for Clostridium difficile would be inadvisable. First, it is not clear that CDAD is reasonably preventable in the majority of cases. Second, from an administrative perspective, it is sometimes hard to distinguish and accurately diagnose CDAD, making it difficult and costly to apply the present on admission indicators. Third, application of CMS’ non-payment policy for complicating conditions to CDAD may create incentives for hospitals to avoid caring for certain at risk populations. Prevention Clostridium difficile is ubiquitous in hospitals, however, it cannot be reasonably prevented even through evidence-based guidelines. Nonetheless, we support the CDC’s guidelines for the prevention of CDAD found at http://www.cdc.gov/ncidod/dhqp/id_CdiffFAQ_HCP.html and at http://www.cdc.gov/ncidod/dhqp/pdf/isolation2007.pdf as cited in the 2008 proposed rule. For example, the literature supports the role of environmental disinfection with unbuffered hypochlorite solutions (diluted 1:10.) 3 There is also support for contact precautions/enteric precautions for diarrhea, isolation, gloves and gowns, and hand hygiene. 4 5 We agree with the CDC that hand washing is essential, as alcohol-based solutions are not effective against Clostridium difficile spores. 6 7 8 Educating hospital staff and patient family and visitors about the

2

Jarvis, William, “National Point Prevalence of Clostridium difficile in U.S. Health Care Facility Inpatients, 2008.” Am J Infect Control, 2009; 37:263-270.

3

Surawicz, CM, “Treatment of Recurrent Clostridium Difficile-Associated Disease,” Nature Clinical Practice Gastroenterology & Hepatology, Nov. 2004, l(1); 32-38. 4 Bartlett, JG and Perl, TM, “The New Clostridium Difficile – What Does It Mean?” N Eng J Med 353; 23, 2503-05. 5 McFarland, LV, “Update on the Changing Epidemiology of Clostridium Difficile-Associated Disease.” Nature Clinical Practice Gastroenterology & Hepatology, January 2008, Vol., 5, No. 1, 40-48. 6 McDonald, LC, et al, “An Epidemic, Toxin Gene-Variant Stain of Clostridium Difficile,” N Eng J Med 353;23, 243341. 7 Bartlett, JG and Perl, TM, “The New Clostridium Difficile – What Does It Mean?” N Eng J Med 353; 23, 2503-05.

disease is also helpful in reducing the spread of disease, 9 but hospitals can only exert so much control over families and visitors. Compliance with CDC guidelines with respect to hand hygiene and “judicious” antibiotic use call into question the “reasonableness” of complete prevention of this pathogen. Increases in hand hygiene compliance for the prevention of the spread of disease have been laudable, but alcoholbased products have played a significant role in this increased compliance rate, potentially complicating efforts to avoid the spread of CDAD. Indeed, the proportion of all hand hygiene episodes performed with soap and water dropped from 90% to 15%, three years after the introduction of alcohol hand gels in one U.S. teaching hospital. 10 The trade-off of higher overall compliance against more focused use of soap and water is one that CMS must consider given that alcohol-based products are effective against the majority of microorganisms other than Clostridium difficile. Appropriate use of antibiotics represents another challenge. Many patients are colonized with Clostridium difficile but have no symptoms. However, exposure to antibiotics that disrupt the colonic microbial flora is the most important risk factor for CDAD. 11 12 About 3% of healthy adults and 20-40% of hospitalized patients are colonized with Clostridium difficile, which, in healthy persons, is metabolically inactive in the spore form. Many patients have Clostridium difficile as an asymptomatic, commensal organism in their intestine on admission that only becomes a problem after they are treated with antibiotics if, in fact, it ever induces symptoms. The pathogen has shown a remarkable ability to adapt itself to the widespread use of new antibiotic agents; almost any type of antimicrobial agent that disrupts the intestinal miroflora can incite the development of CDAD. 13 The most commonly implicated antibiotic in the 1970s was clindamycin, and in the 1980s, it was cephalosporins. 14 Indeed, according to recent AHRQ data, four out of the top twenty most common principle diagnoses which occur in association with CDAD are infections (sepsis, pneumonia, urinary tract infection, and skin infection) where antibiotic use would be expected and difficult to avoid. 15 More recent evidence shows that antibiotic policies may be even more challenged by the newer more virulent strain of CDAD, known as B1/NAP1. An important method of controlling past outbreaks of CDAD has been restriction on the use of antimicrobial agents implicated as risk factors for the disease. Whether a large-scale restriction on the use of these antimicrobial agents could slow the geographic spread of the new strain is unknown. Because flouroquinlones have become a mainstay in the treatment of several common infections, a large-scale restriction on the use of these drugs would be very challenging. 16

8

Lawrence, S.J., “Contemporary management of Clostridium Difficile-Associated Disease,” Gastroenterology & Endoscopy News Special Edition, 2007, 35-40. 9 Brandt, LB “What’s New in Ischemic and C. Difficile Colitis?” Presentation March 7, 2008 at ACG Regional Course, New York, New York. 10 Shen, EP and Surawicz, CM, “The Changing Face of Clostridium Difficile: What Treatment Options Remain?” Am. J. Gastroenterology, Dec. 2007, 102 (12): 2789-92. 11 Lawrence, S.J., “Contemporary management of Clostridium Difficile-Associated Disease,” Gastroenterology & Endoscopy News Special Edition, 2007, 35-40. 12 McFarland, LV, “Update on the Changing Epidemiology of Clostridium Difficile-Associated Disease.” Nature Clinical Practice Gastroenterology & Hepatology, January 2008, 5 (1): 40-48. 13 McFarland, LV, “Update on the Changing Epidemiology of Clostridium Difficile-Associated Disease.” Nature Clinical Practice Gastroenterology & Hepatology, January 2008, , 5 (1): 40-48. 14 Bartlett, JG and Perl, TM, “The New Clostridium Difficile – What Does It Mean?” N Eng J Med 353 (23): 2503-05. 15 Elixhauser, A. (AHRQ), and Jhung, MA. (Centers for Disease Control and Prevention). Clostridium DifficileAssociated Disease in U.S. Hospitals, 1993–2005. HCUP Statistical Brief #50. April 2008. Agency for Healthcare Research and Quality, Rockville, MD. Accessed at http://www.hcup-us.ahrq.gov/reports/statbriefs/sb50.pdf on May 21, 2008. 16 McDonald, LC, et al, “An Epidemic, Toxin Gene-Variant Stain of Clostridium Difficile,” N Eng J Med 353; 23, 2433-41.

Aggressive CDAD control policies at the best hospitals have successfully decreased, but not eliminated, the incidence of CDAD. For instance, the University of Pittsburgh Medical Center developed a program consisting of education, increased and early case finding, expanded infection-control measures, development of a Clostridium difficile infection management team, and microbial management. The aggregate rate of Clostridium difficile infection decreased from 7.2 infections per 1000 (9.4 during a peak.) hospital discharges to 4.8 infections per 1,000 hospital discharges and, later, to 3.0 infections per 1,000 hospital discharges. While compliance with hand hygiene and isolation were not perfect (the rates of compliance with hand hygiene and isolation were 75% and 68% respectively), 17 the fact that the practices were being studied and part of a focused project would likely increase compliance over what would otherwise be expected. It is not clear that payment incentives could drive the rate of compliance any higher. Research has demonstrated that there is more to be learned in order to prevent the incidence of CDAD. We note that more complete compliance with CDC guidelines would help to reduce the incidence of CDAD but not eradicate it entirely. In its March 2009 “Multidrug-Resistant Organism & Clostridium difficile-Associated Disease (MDRO/CDAD) Module” to assist providers in reporting CDAD cases outlined in existing guidelines and to better inform infection control staff, CDC writes “Current CDC definitions for healthcare-associated infections, while adequate for site of infection, do not take into account the special characteristics of disease caused by C. difficile; although CDAD represents a subset of gastroenteritis and gastrointestinal tract infections, specific standard definitions for CDI(CDAD) should be incorporated to obtain a more complete understanding of how C. difficile is being transmitted in a healthcare facility.” 18 We must discover the root of the problem before learning how to reasonably prevent the disease. Indeed, a recent study suggests that researchers have been focusing on the wrong toxin (toxin A) when treating CDAD when its virulence may stem from toxin B. 19 As the study’s co-authors conclude, the “study has major implication for the future development of treatments and preventive measures for c. diff” and the “more you can understand the way an organism causes disease, the better you can target treatment or preventive measures.” 20 In deciding to exclude CDAD from the list of hospital–acquired infections list in 2008, CMS stated that it would consult with CDC regarding evidence-based guidelines. As noted above, our societies support CDC’s guidance and have independently developed evidence-based guidelines to reduce the incidence of CDAD. However, there is a difference in having the capability to reduce incidences of CDAD versus the ability to prevent the occurrence of CDAD altogether. The fact that CMS rightfully chose to exclude CDAD from the list of hospital-acquired infections in 2007 and 2008 -- and CDC needs more information to update prevention guidelines -- suggests that CMS recognizes this difference between reduction and prevention. While we understand that consumers and purchasers wish to include CDAD as an hospital-acquired condition, we also ask CMS to continue recognizing the difference in what a certain population believes is preventable versus what science concludes is preventable. Since it is still unclear as to whether CDAD is “reasonably preventable,” we believe the standards under the DRA are not met and request that CDAD again be excluded from the list of hospital-acquired infections for the FY 2012 and subsequent years’ payment determinations.

Diagnosing CDAD Poses Challenges to the Present on Admission Scheme

17

Muto, CA et al, “Control of an Outbreak of Infection with the Hypervirulent Clostridium Difficile BI Strain in a University Hospital Using a Comprehensive Bundle Approach,” Clin Infect. Dis., 2007 Nov 15; 45(1): 1274-6. 18 CDC, Multidrug-Resistent Organism & Clostridium diffcile-Associated Disease (MDRO/CDAD) Module, March, 2009, see http://www.cdc.gov/nhsn/PDFs/pscManual/12pscMDRO_CDADcurrent.pdf. 19 Lyras, Dena, “Toxin B is essential for virulence of Clostridium difficile.” Nature, April 30, 2009, 458, 1176-1179. 20 Infection Control Today, “Study Reveals What Makes C. diff Superbug Deadly,” March 2, 2009, see http://www.infectioncontroltoday.com/hotnews/study-reveals-superbug-deadliness.html.

In order to implement the requirements of the DRA, CMS must be able to determine whether or not a specific condition was present on admission. Despite improvements in diagnosis in recent years, Clostridium difficile poses unique challenges to determining whether or not it was present on admission. For several reasons, even in the best hospitals, there can be delays in diagnosing and treating both recurrent CDAD and initial CDAD. 21 First, CDAD can mimic the more common "benign" antibiotic-associated diarrhea that is not caused by Clostridium difficile. 22 Thus, many people who have diarrhea for another reason will look like they have CDAD regardless of an underlying "food poisoning" or virus, or other cause. Conversely, patients can be infected with this microorganism and have no symptoms of colitis. They, therefore, are not tested for the toxin. Indeed, it is estimated that up to two-thirds of hospitalized patients could be infected with Clostridium difficile. 23 Patients – even asymptomatic carriers -- infected with the pathogen who are admitted to healthcare facilities such as hospitals can transmit the toxin to other susceptible patients in the healthcare facility and can be important vectors in outbreaks. The diagnosis of CDAD is, in general, based on the patient’s symptoms, a history of antibiotic use, clinical suspicion as well as stool testing. The most widely used test for diagnosing Clostridium difficile colitis is a test that detects toxins produced by Clostridium difficile in a sample of stool. There are two different toxins -- toxin A and toxin B -- both capable of causing colitis. Accurate tests for both toxins are available commercially for use in all laboratories. However, these tests are imperfect and false positive and false negatives are not uncommon; for example, false-negative results have been reported to occur in 29-56% of cases. 24 The gold standard for the diagnosis of CDAD is a cytotoxin assay. This test is highly sensitive and specific, but it is challenging to perform, and results are not available for 24 to 48 hours, 25 further complicating efforts to determine if the toxin was present on admission in a timely manner. Additionally, the new hyper-virulent strain, which is growing in incidence and severity, cannot be detected by the standard stool assays available in most labs. 26 Therefore, other tests such as flexible sigmoidoscopy and colonoscopy often are necessary to look for the pseudomembranes that are characteristic of CDAD. AHRQ data makes clear that one of the challenges in accurately diagnosing CDAD is that it is not unusual for patients to have multiple co-morbidities. The AHRQ found that hospitalized patients with CDAD cases had over ten diagnoses compared with six diagnoses for cases without CDAD. 27 Further complicating accurate diagnosis of CDAD is that while symptoms typically occur within 48 hours of infection, patients infected in the hospital with Clostridium difficile in the hospital usually become infected within three weeks of admission, but the onset of symptoms can be delayed two to three months. 28 While most cases occur on days four to nine of antibiotic therapy,

21

Scheurer, D, “Diagnostic and Treatment Delays in Recurrent Clostridium Difficile-Associated Diseases,” J Hosp Med, 2008 March; 3(2): 15 6-9. 22 R. Fekety and A. B. Shah, “Diagnosis and treatment of Clostridium difficile colitis,“ JAMA, Jan 1993; 269: 71 – 75 23 Brandt, LB “What’s New in Ischemic and C. Difficile Colitis?” Presentation March 7, 2008 at ACG Regional Course, New York, New York. 24 McFarland, LV, “Update on the Changing Epidemiology of Clostridium Difficile-Associated Disease.” Nature Clinical Practice Gastroenterology & Hepatology, January 2008, 5(1) : 40-48 25 Schroeder, MS, “Clostridium Difficile-Associated Diarrhea,” American Family Physician, 1 March 2005, 71(5); 92128. 26 Bartlett, JG and Perl, TM, “The New Clostridium Difficile – What Does It Mean?” N Eng J Med 353 (23): 2503-05. 27 Elixhauser, A. (AHRQ), and Jhung, MA. (Centers for Disease Control and Prevention). Clostridium DifficileAssociated Disease in U.S. Hospitals, 1993–2005. HCUP Statistical Brief #50. April 2008. Agency for Healthcare Research and Quality, Rockville, MD. http://www.hcup-us.ahrq.gov/reports/statbriefs/sb50.pdf 28 McFarland, LV, “Update on the Changing Epidemiology of Clostridium Difficile-Associated Disease.” Nature Clinical Practice Gastroenterology & Hepatology, January 2008, 5(1): 40-48.

CDAD can occur up to eight weeks after the discontinuation of antibiotics. 29 In cases of delayed onset of CDAD, it may be difficult to determine if the pathogen was acquired during a hospital stay. Even in those instances where the toxin was acquired at the hospital, it would not be present on admission and hospitals would not be “docked” for it even though the hospital was the likely source of the pathogen.

Certain Populations Are Uniquely Vulnerable The concept of not paying for complications that may be unavoidable despite safe practice is discriminatory and could end up hurting vulnerable patients. Specifically, patients who are older, are immuno-compromised, or are medically underserved are more susceptible to infection and other complications. Application of this policy could exacerbate existing disincentives for hospitals to provide care to these populations by encouraging hospitals to erect barriers to their admission. Medicare beneficiaries who have recently resided in a nursing home are at a disproportionate risk of having been exposed to CDAD. The lack of risk adjustment for this population is another weakness of the proposed policy. The subsequent diagnosis of CDAD for this subset of the Medicare population is not always possible upon admission to the hospital due to the variable incubation periods and the cost of a screening program for all inpatient admissions. While we support CMS’ efforts to improve the quality of care provided to Medicare beneficiaries across all settings, it is not reasonable to hold the inpatient hospital liable for a condition acquired in a different setting, one which may not even be detectable upon the patient’s admission into their setting. In the case of CDAD, it is important to note that certain populations are at elevated risk for the disease, particularly those with inflammatory bowel disease (IBD), those on proton pump inhibitors (PPIs), as well as older individuals, and those with co-morbid disease, are immunosupressed, hypoalbuminemic or with low levels of antitoxin A and B antibodies. 30 31 In fact, the CDC recognizes that the risk for CDAD increases not only in relation to antibiotic exposure but also to gastrointestinal surgery/manipulation, long length of stay in healthcare settings, a serious underlying illness, immunocompromising conditions and advanced age. 32 Even in the best hospitals, it would be difficult to completely avoid nosocomial outbreaks of Clostridium difficile in these populations. With regard to PPIs, recent data indicates that the risk of CDAD in hospitalized patients receiving antibiotics may be compounded by exposure to PPI therapy. The inhibition of gastric acid may impact the defense against ingested bacteria. 33 For IBD patients, it is important to note that relapse of IBD has been associated with Clostridium difficile and that the toxin is an exacerbating factor for patients with IBD. The incidence of CDAD in patients with IBD appears to be increasing, as is the total percentage of patients with CDAD who also have IBD. The precise cause of the correlation between CDAD and IBD is unclear. It may be due to more sensitive tests for Clostridium difficile toxins A and B, to increased awareness of the need for testing, to

29

Schroeder, MS, “Clostridium Difficile-Associated Diarrhea,” American Family Physician, 1 March 2005, 71(5) 92128. 30 Brandt, LB “What’s New in Ischemic and C. Difficile Colitis?” Presentation March 7, 2008 at ACG Regional Course, New York, New York. 31 Schroeder, MS, “Clostridium Difficile-Associated Diarrhea,” American Family Physician, 1 March 2005, 71 (5): 921-28. 32 CDC, Information for Healthcare Providers, Released August 2004; Updated 07/22/2005, see http://www.cdc.gov/ncidod/dhqp/id_CdiffFAQ_HCP.html 33 Yearsley, A, et al (2006) “Proton pump inhibitor therapy is a risk factor for Clostridium difficile-associated diarrhea, Alimentary Pharmacology & Therapeutics 2006 24 (4) , 613–619.

increased use of PPIs, antibiotics or immunomodulators, to higher hospital bed occupancy or to the underlying IBD disease. 34 We would urge CMS not to add Clostridium difficile to its list of quality measures beginning with the FY 2012 payment determination.

Conclusion In conclusion, the ACG, AGA and ASGE urge CMS not to add Clostridium difficile to its list of hospital-acquired conditions for which additional payment as a complicating condition would not be available. Evidence has thus far concluded that the disease is not reasonably preventable. Adding it to the list of new quality measures would create a very expensive and unworkable situation for CMS, hospitals, physicians and patients. Nonetheless, we would welcome opportunities to work with CMS and its sister agencies within HHS such as CDC and AHRQ to reduce the overall incidence of CDAD. Such a reduction may be achievable through adherence to available guidelines. Additional research may identify an expected level of CDAD that can occur despite compliance to the highest level of prevention control guidelines. Such research must encompass the emergence and potentially changing nature of the hyper-virulent strain of Clostridium difficile. We look forward to working with you on this vital public health issue. If we can be of assistance, please do not hesitate to contact Brad Conway, Vice President, Public Policy, ACG at 301.263.9000 or [email protected]; or Anne Marie Bicha, Director of Regulatory Affairs, AGA, at 240.482.3223 or abicha@gastro2org; or Sheila Madhani, Consultant to ASGE, at 202.419.2510 or [email protected].

34

Irving, PM. and Gibson, PR, “Infections and IBD.” Nature Clinical Practice: Gastroenterology & Hepatology,” January 2008, 5(1): 18-27.

Respectfully Submitted,

Eamonn M.M. Quigley, M.D., FACG President, American College of Gastroenterology

Jacques Van Dam, M.D., PhD, FASGE President, American Society for Gastrointestinal Endoscopy

Robert Sandler, M.D. PhD, AGAF Chair, American Gastroenterological Association