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Original Research |

A Comprehensive Care Management Program to Prevent Chronic Obstructive Pulmonary Disease Hospitalizations: A Randomized, Controlled Trial

Vincent S. Fan, MD, MPH; J. Michael Gaziano, MD, MPH; Robert Lew, PhD; Jean Bourbeau, MD, MSc; Sandra G. Adams, MD, MS; Sarah Leatherman, MS; Soe Soe Thwin, PhD, MS; Grant D. Huang, PhD, MPH; Richard Robbins, MD; Peruvemba S. Sriram, MD; Amir Sharafkhaneh, MD; M. Jeffery Mador, MD; George Sarosi, MD; Ralph J. Panos, MD; Padmashri Rastogi, MD; Todd H. Wagner, PhD; Steven A. Mazzuca, PhD; Colleen Shannon, MPH; Cindy Colling, RPH, MS; Matthew H. Liang, MD, MPH; James K. Stoller, MD, MS; Louis Fiore, MD, MPH; and Dennis E. Niewoehner, MD
[+] Article and Author Information

From the Veterans Affairs Puget Sound Health Care System, Seattle, Washington; Veterans Affairs Boston Healthcare System and Brigham and Women's Hospital, Boston, Massachusetts; Montreal Chest Institute, Montreal, Quebec, Canada; South Texas Veterans Health Care System, San Antonio, Texas; Department of Veterans Affairs Cooperative Studies Program, Washington, DC; Phoenix Veterans Affairs Medical Center, Phoenix, Arizona; North Florida/South Georgia Veterans Health System, Gainesville, Florida; Michael E. DeBakey Veterans Affairs Medical Center, Houston, Texas; Veterans Affairs Western New York Healthcare System, Buffalo, New York; Cincinnati Veterans Affairs Medical Center, Cincinnati, Ohio; Dallas Veterans Affairs Medical Center, Dallas, Texas; Veterans Affairs Palo Alto Healthcare System, Menlo Park, California; Richard L. Roudebush Veterans Affairs Medical Center and Indiana University School of Medicine, Indianapolis, Indiana; Veterans Affairs Cooperative Studies Program Clinical Research Pharmacy Coordinating Center, Albuquerque, New Mexico; Minneapolis Veterans Affairs Healthcare System, Minneapolis, Minnesota; and The Cleveland Clinic, Cleveland, Ohio.

Disclaimer: The views expressed in this article are those of the authors and do not necessarily represent the views of the Department of Veterans Affairs. Vincent S. Fan, MD, MPH; J. Michael Gaziano, MD, MPH; and Dennis E. Niewoehner, MD, had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis.

Financial Support: By the Cooperative Studies Program (CSP #560), Veterans Affairs Office of Research and Development.

Potential Conflicts of Interest: Disclosures can be viewed at www.acponline.org/authors/icmje/ConflictOfInterestForms.do?msNum=M11-1426.

Reproducible Research Statement:Study protocol: Available from the data coordinating center at the Massachusetts Veterans Epidemiology Research and Information Center (MAVERIC) (e-mail, mailto:MAVERIC-Info@va.gov). Statistical code: Available from Dr. Lew (e-mail, mailto:robert.lew2@va.gov). Data set: Not available.

Requests for Single Reprints: Vincent S. Fan, MD, MPH, Health Services Research and Development Center of Excellence, Veterans Affairs Puget Sound Health Care System, 1600 South Columbian Way, Seattle, WA 98108; e-mail, mailto:vincent.fan@va.gov.

Current Author Addresses: Dr. Fan: Veterans Affairs Puget Sound Health Care System, 1100 Olive Way, Suite 1400, Seattle, WA 98101.

Drs. Gaziano, Lew, Thwin, and Fiore; Ms. Leatherman; and Ms. Shannon: Veterans Affairs Boston Healthcare System, 150 South Huntington Avenue, Boston, MA 02130.

Dr. Bourbeau: Montreal Chest Institute, 3650 St-Urbain, Montreal, Quebec H2X 2P4, Canada.

Dr. Adams: South Texas Veterans Health Care System, 7400 Merton Minter, San Antonio, TX 78229.

Dr. Huang: Department of Veterans Affairs Cooperative Studies Program, 810 Vermont Avenue NW, MS-10P9CS, Washington, DC 20420.

Dr. Robbins: Phoenix Veterans Affairs Medical Center, 650 East Indian School Road, Phoenix, AZ 85012.

Dr. Sriram: North Florida/South Georgia Veterans Health System, 1601 SW Archer Road, Gainesville, FL 32608.

Dr. Sharafkhaneh: Michael E. DeBakey Veterans Affairs Medical Center, 2002 Holcombe Boulevard, Houston, TX 77030.

Dr. Mador: Veterans Affairs Western New York Healthcare System, 3495 Bailey Avenue, Buffalo, NY 14215.

Drs. Sarosi and Niewoehner: Minneapolis Veterans Affairs Healthcare System, 1 Veterans Drive, Minneapolis, MN 55417.

Dr. Panos: Cincinnati Veterans Affairs Medical Center, 3200 Vine Street, Cincinnati, OH 45220.

Dr. Rastogi: Dallas Veterans Affairs Medical Center, 4500 South Lancaster Road, Mail Code IIIE, Dallas, TX 75216.

Dr. Wagner: Veterans Affairs Palo Alto Healthcare System, 795 Willow Road, 152-MPD, Menlo Park, CA 94025.

Dr. Mazzuca: Indiana University School of Medicine, Long Hospital, Room 545, 1110 West Michigan Street, Indianapolis, IN 46202-5100.

Ms. Colling: Veterans Affairs Cooperative Studies Program Clinical Research Pharmacy Coordinating Center, 2401 Centre Avenue SE, Albuquerque, NM 87106-4180.

Dr. Liang: Department of Medicine, Brigham and Women's Hospital, 75 Francis Street, PBB3, Boston, MA 02115.

Dr. Stoller: The Cleveland Clinic, 9500 Euclid Avenue, NA22, Cleveland, OH 44195.

Author Contributions: Conception and design: V.S. Fan, J.M. Gaziano, R. Lew, J. Bourbeau, S.G. Adams, G.D. Huang, T.H. Wagner, S.A. Mazzuca, M.H. Liang, J.K. Stoller, L. Fiore, D.E. Niewoehner.

Analysis and interpretation of the data: V.S. Fan, J.M. Gaziano, R. Lew, J. Bourbeau, S. Leatherman, S.S. Thwin, G.D. Huang, T.H. Wagner, S.A. Mazzuca, M.H. Liang, J.K. Stoller, D.E. Niewoehner.

Drafting of the article: V.S. Fan, R. Lew, G.D. Huang, R.J. Panos, T.H. Wagner, S.A. Mazzuca, J.K. Stoller, D.E. Niewoehner.

Critical revision of the article for important intellectual content: V.S. Fan, J.M. Gaziano, R. Lew, J. Bourbeau, S.G. Adams, G.D. Huang, A. Sharafkhaneh, M.J. Mador, S.A. Mazzuca, M.H. Liang, L. Fiore, D.E. Niewoehner.

Final approval of the article: V.S. Fan, J.M. Gaziano, R. Lew, J. Bourbeau, S.G. Adams, G.D. Huang, P.S. Sriram, A. Sharafkhaneh, M.J. Mador, G. Sarosi, R.J. Panos, T.H. Wagner, S.A. Mazzuca, C. Shannon, M.H. Liang, J.K. Stoller, L. Fiore, D.E. Niewoehner.

Provision of study materials or patients: V.S. Fan, J.M. Gaziano, S.G. Adams, R. Robbins, P.S. Sriram, A. Sharafkhaneh, M.J. Mador, G. Sarosi, R.J. Panos, P. Rastogi, L. Fiore.

Statistical expertise: R. Lew, S. Leatherman, S.S. Thwin.

Obtaining of funding: V.S. Fan, J.M. Gaziano, R. Robbins, P. Rastogi, T.H. Wagner, L. Fiore, D.E. Niewoehner.

Administrative, technical, or logistic support: J.M. Gaziano, R. Lew, S.G. Adams, T.H. Wagner, C. Shannon, C. Colling, M.H. Liang, L. Fiore.

Collection and assembly of data: V.S. Fan, J.M. Gaziano, S.G. Adams, P.S. Sriram, A. Sharafkhaneh, M.J. Mador, G. Sarosi, R.J. Panos, P. Rastogi, T.H. Wagner, C. Colling, D.E. Niewoehner.


Ann Intern Med. 2012;156(10):673-683. doi:10.7326/0003-4819-156-10-201205150-00003
Text Size: A A A

Background: Improving a patient's ability to self-monitor and manage changes in chronic obstructive pulmonary disease (COPD) symptoms may improve outcomes.

Objective: To determine the efficacy of a comprehensive care management program (CCMP) in reducing the risk for COPD hospitalization.

Design: A randomized, controlled trial comparing CCMP with guideline-based usual care. (ClinicalTrials.gov registration number: NCT00395083)

Setting: 20 Veterans Affairs hospital-based outpatient clinics.

Participants: Patients hospitalized for COPD in the past year.

Intervention: The CCMP included COPD education during 4 individual sessions and 1 group session, an action plan for identification and treatment of exacerbations, and scheduled proactive telephone calls for case management. Patients in both the intervention and usual care groups received a COPD informational booklet; their primary care providers received a copy of COPD guidelines and were advised to manage their patients according to these guidelines. Patients were randomly assigned, stratifying by site based on random, permuted blocks of variable size.

Measurements: The primary outcome was time to first COPD hospitalization. Staff blinded to study group performed telephone-based assessment of COPD exacerbations and hospitalizations, and all hospitalizations were blindly adjudicated. Secondary outcomes included non-COPD health care use, all-cause mortality, health-related quality of life, patient satisfaction, disease knowledge, and self-efficacy.

Results: Of the eligible patients, 209 were randomly assigned to the intervention group and 217 to the usual care group. Citing serious safety concerns, the data monitoring committee terminated the intervention before the trial's planned completion after 426 (44%) of the planned total of 960 patients were enrolled. Mean follow-up was 250 days. When the study was stopped, the 1-year cumulative incidence of COPD-related hospitalization was 27% in the intervention group and 24% in the usual care group (hazard ratio, 1.13 [95% CI, 0.70 to 1.80]; P = 0.62). There were 28 deaths from all causes in the intervention group versus 10 in the usual care group (hazard ratio, 3.00 [CI, 1.46 to 6.17]; P = 0.003). Cause could be assigned in 27 (71%) deaths. Deaths due to COPD accounted for the largest difference: 10 in the intervention group versus 3 in the usual care group (hazard ratio, 3.60 [CI, 0.99 to 13.08]; P = 0.053).

Limitations: Available data could not fully explain the excess mortality in the intervention group. Ability to assess the quality of the educational sessions provided by the case managers was limited.

Conclusion: A CCMP in patients with severe COPD had not decreased COPD-related hospitalizations when the trial was stopped prematurely. The CCMP was associated with unanticipated excess mortality, results that differ markedly from similar previous trials. A data monitoring committee should be considered in the design of clinical trials involving behavioral interventions.

Primary Funding Source: Veterans Affairs Cooperative Study Program.

Figures

Grahic Jump Location
Figure 2.

Failure curves for chronic obstructive pulmonary disease hospitalization (top) and mortality (bottom) until termination of study intervention, according to study assignment.

CCMP = comprehensive care management program.

Grahic Jump Location

Tables

References

Letters

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Comments

Submit a Comment
Need a Comprehensive Care Management Plan That Includes Many Components
Posted on May 29, 2012
Gerard J., Criner, MD, FACP
Conflict of Interest: None Declared

The study by Fan et al underscores several important issues that affect the care of the COPD patient and highlights the potential dangers associated with attempts to decrease costs in treating patients with this disease. (1) As illustrated by this study, COPD patients are ill, have significant multiple life-threatening comorbidities, frequently live alone and have a high % of cognitive dysfunction and depression. COPD patients require complex treatments that include multiple inhaled and oral medications, oxygen therapy and additional interventions needed to treat escalating symptoms that herald an exacerbation. In Fan's study, more patients in the intervention group were not currently married and had a greater degree of ischemic heart disease, congestive heart failure, peripheral vascular disease and finally depression. To achieve success, these factors necessitate a comprehensive care management plan that includes intensive education about the nature of the primary disease and comorbidities, ongoing regular contact with a knowledgeable supervising care team and close monitoring of subject adherence to the action plan that triggers prompt recognition of escalating symptoms and timely treatment.

As reported by the investigators, patients in the comprehensive care management program waited almost a week before taking medications as recommended by the action plan and did not take medications any sooner than the usual care group.(1) An average of 2.5 exacerbations per patient- year were treated with prednisone in the intervention arm compared with 2.1 with usual care (p =0.011) and the average delay to prednisone treatment after symptoms began was 6.4 days in the intervention group and 7.7 with usual care (p= 0.48). An average of 2.7 exacerbations per patient -year were treated with an antibiotic compared with 2.5 in the usual care group (p= 0.118) and the average delay to antibiotic treatment was 7.0 days in the intervention group and 6.8 days with usual care (p=0.84). The study care managers who instructed the cohort had various backgrounds that included nurses, respiratory therapists, study coordinators and medical assistants. Their background and skill in managing complexly ill COPD patients under a variety of conditions is unclear. More patients in the interventional arm had fatal COPD related events and less urgent ER visits suggesting less intense treatment received by the comprehensive care management arm. These data suggest that the comprehensive care management plan failed in its intent to provide timely care for patients with worsening symptoms of an exacerbation.

By contrast, the prior study conducted by Bourbeau had a robust comprehensive disease management plan that was hallmarked by home visits and a sophisticated group of case managers (nurses and respiratory therapist) that interacted frequently with their subject group. (2) The case managers provided one hour per week of home education for 7-8 weeks and then performed weekly phone calls for 8 weeks and then monthly phone calls thereafter. It emphasized the prompt initiation of an antibiotic and steroid for exacerbation treatment and safeguards to call the case manager or treating physicians if symptoms worsened. Similarly, Rice et al paid special attention to self-treatment of an exacerbation with each patient receiving an individualized written action plan and access to a 24-hour VA hotline number.(3) Supervision was provided at each center by a respiratory therapist case manager. As a result, patients in the disease management arm of the Rice study used prednisone and antibiotics at least twice as often as did subjects in the usual care arm. In contrast to the study by Fan, both of the above studies showed statistically significant and clinically meaningful improvements in patient's outcomes with the comprehensive management programs that used self-management strategies for exacerbation treatment.(2, 3)

This study adds to the current body of literature by highlighting the complexity and seriousness of illness embodied by COPD patients prone to exacerbations and the necessity for detailed, easily accessible, and highly interactive communication with highly skilled practitioners to create a successful outpatient program.(1) Their data when viewed in light of the prior studies suggests that the action plan educational program, monitoring of study subject adherence to the action plan and subject knowledge about what to do and where to go for urgent treatment needs to be very robust when conducted in this elderly patient group with severe COPD and multiple comorbidities who frequently live alone and commonly have cognitive dysfunction and underlying depression. Future studies and care plans focused on reducing cost to treat in COPD by developing "hospital at home" or "self care for exacerbation" programs need to take these factors into consideration.

References

1. Fan VS, Gaziano JM, Lew R, Bourbeau J, Adams SG, Leatherman S, et al. A Comprehensive Care Management Program to Prevent Chronic Obstructive Pulmonary Disease Hospitalizations: A Randomized, Controlled Trial. Ann Intern Med. 2012;156(10):673-83.

2. Bourbeau J, Julien M, Maltais F, Rouleau M, Beaupre A, Begin R, et al. Reduction of hospital utilization in patients with chronic obstructive pulmonary disease: a disease-specific self-management intervention. Arch Intern Med. 2003;163(5):585-91.

3. Rice KL, Dewan N, Bloomfield HE, Grill J, Schult TM, Nelson DB, et al. Disease management program for chronic obstructive pulmonary disease: a randomized controlled trial. Am J Respir Crit Care Med. 2010;182(7):890- 6.

Conflict of Interest:

None declared

Overgeneralizing the Importance of Data Monitoring Committees
Posted on May 30, 2012
Boadie W, Dunlop, Assistant Professor
Emory University School of Medicine
Conflict of Interest: None Declared

Fan et al. assert that the action by the Data Monitoring Committee (DMC) to halt their behavioral intervention trial for chronic obstructive pulmonary disease indicates that "it should not be assumed that there are minimal safety concerns in behavioral or educational interventions." (1) This conclusion is not justified from their study. The unexpectedly higher death rates in the intervention group in this trial can derive only from 3 possible sources: 1) baseline differences of factors predictive of mortality between the randomized groups; 2) chance variation; or 3) harms of providing the intervention. Explanations 1 and 2 cannot be predicted nor controlled, and the unfortunate demise of trial subjects affected by these factors would have occurred regardless of their participation in the trial; the DMC's decision to end the trial could not have produced any additional safety for these patients.

At baseline, the intervention group had greater rates of conditions associated with higher likelihood of death, including cardiac disease, peripheral artery disease, and depression. They also were more likely to be unmarried, which suggests they had less social support and lower levels of health vigilance compared to participants with a spouse (particularly considering that the sample was 97% male). These baseline differences likely explain some, but perhaps not all of the excess mortality in the intervention group.

So was the trial's "behavioral" intervention harmful? Here it must be noted that this trial did not evaluate a typical behavioral or educational intervention. In addition to provision of information, patients in this trial were instructed to self-initiate treatment with prescription medications - an action far beyond the goal of most educational trials. DMC monitoring was appropriate for this study specifically because of this treatment component to the intervention. It is inappropriate to generalize from this trial to all educational or behavioral intervention trials, which do not involve patients autonomously changing their medication regimens. To require a DMC and all its associated reporting requirements would provide very little, if any, additional safety benefit for the overwhelming majority of education and behavioral intervention studies. Indeed, if research regulators become concerned that "a little knowledge is a dangerous thing," then a great deal of common clinical practice is cast into doubt. Moreover, the authors' broad assertion of the need for DMCs could impede quality improvement efforts within institutions, burdening them with unnecessary reporting requirements that do nothing to enhance safety.

References

1. Fan VS, Gaziano JM, Lew R, Bourbeau J, Adams SG, Leatherman S, et al. A Comprehensive Care Management Program to Prevent Chronic Obstructive Pulmonary Disease Hospitalizations: A Randomized, Controlled Trial. Ann Intern Med. 2012;156(10):673-83.

Conflict of Interest:

None declared

Letter to the Editor Re: A Comprehensive Car Management Program to Prevent Chronic Obstructive Pulmonary Disease Hospitalizations
Posted on June 14, 2012
R. William Vandivier, MD, Patricia B. Koff, RRT, MEd, and Derek J. Linderman, MD
COPD Center, Division of Pulmonary Sciences and Critical Care Medicine, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, and Robert Bosch Healthcare, Palo Alto, CA 94303
Conflict of Interest: None Declared

We were disappointed at the results of a comprehensive care management program for chronic obstructive pulmonary disease (COPD) reported by Fan et al.(1). Subjects underwent extensive education and were given an individualized action plan that advised them to initiate therapy within 48 hours of symptoms and to contact their care coordinator if therapy was not effective. The intervention had minimal to no effect on treatment and worsened mortality. As pointed out by the authors, treatment delays are common in COPD and these delays result in worse clinical outcomes. We would be interested to know how many subjects contacted coordinators at symptoms onset, and whether they contacted coordinators as directed when symptoms worsened or became persistent.

We have performed two published(2, 3) and two unpublished studies(4) (NCT01044927) of proactive integrated care (PIC) in 652 patients with COPD. PIC differs from traditional integrated care in that it includes a remote monitoring platform using the Health Buddy® (Robert Bosch Healthcare). Subjects participate in short daily sessions, during which they receive education, answer symptom-based questions and enter objective measurements(2-4). Subjects are then categorized into three color-coded groups: green being stable, yellow advising caution and red indicating a possible decline in health status. Coordinators call all patients with red flags and use discretion in contacting patients with yellow flags. When red flags appear, all subjects are advised by the Health Buddy® to call their coordinator. However, the majority (i.e. 47-78%) fail to make this critical call (2, 3).

Linderman et al. enrolled 100 COPD subjects and monitored them for three months(3). One red flag was present in 55% of exacerbations and a combination of yellow flags was present in the other 45%(3). The Health Buddy advised all red-flagged patients to call their coordinator, but only 53% heeded this advice. A larger trial by Koff et al. enrolled 403 COPD subjects and monitored them for nine months(4). The majority of red-flagged subjects did not call their coordinator, but a coordinator-led intervention occurred nonetheless. In contrast to the study by Fan(1), the Koff study showed a trend toward decreased mortality(4).We suggest that future clinical trials of integrated care for COPD include a simple, low-cost, interactive monitoring platform to allow for early detection and treatment of COPD exacerbations. Proactive, early-warning systems that do not entirely rely on patient recognition and action could make the difference for patients that may not fully realize the severity of their disease.

References

1. Fan VS, Gaziano JM, Lew R, Bourbeau J, Adams SG, Leatherman S, et al. A Comprehensive Care Management Program to Prevent Chronic Obstructive Pulmonary Disease Hospitalizations: A Randomized, Controlled Trial. Ann Intern Med. 2012;156(10):673-83.

2. Koff PB, Jones RH, Cashman JM, Voelkel NF, Vandivier RW. Proactive integrated care improves quality of life in patients with COPD. Eur Respir J. 2009;33(5):1031-8.

3. Linderman DJ, Koff PB, Freitag TJ, Min SJ, Vandivier RW. Effect of integrated care on advanced chronic obstructive pulmonary disease in high-mortality rural areas. Arch Intern Med. 2011;171(22):2059-61.

4. Koff PB, Min SJ, Freitag TJ, James SS, Keith RL, Kveton C, et al. Proactive Integrated Care Reduces Critical Care and Improves Quality of LIfe in COPD. Am. J. Respir. Crit. Care Med. 2009;179:A3100.

Response to Letter to the Editor by Vandivier et al.
Posted on July 20, 2012
Vincent S. Fan, MD MPH, Dennis E. Niewoehner, MD, Robert Lew, PhD
Conflict of Interest: None Declared

Response:We thank Dr. Vandivier and colleagues for their thoughtful comments on our study, and for focusing on the communication between patients and their case managers in care management programs for COPD. In the education sessions in our trial, the case managers reviewed the individualized action plan that advised patients to start therapy within 48 hours of developing symptoms consistent with an exacerbation1. As was pointed out, patients were also advised to call their case manager when they started treatment for an exacerbation, and if their symptoms were not improving.As reported in the paper, during the first 12 months of follow-up there 600 exacerbations reported by the 217 patients in the intervention group. Case managers pro-actively contacted patients at regular intervals during study follow-up. Case managers also completed a case report form for each unplanned contact between patients and case managers during this time period. During the study, 27 intervention patients contacted their case manager because they were having an exacerbation, 5 of these contacts were in-person and 22 via telephone call. An additional 19 patients contacted case-managers for reasons other than an exacerbation during the follow-up period. Case managers were available during business hours, and patients were instructed to call the existing 24-hour telenurse line if they had breathing problems at night or during the weekend; we did not collect data on after-hours telenurse communications. Although we were not able to explain the mortality difference seen between the intervention and control groups, Dr. Vandivier has highlighted the role of ongoing communication between patients and the health care team in care management interventions, as well as the different approaches to symptom monitoring that can be included in these interventions. While the trial was not intended to be explanatory in nature, understanding mechanisms in behavioral or educational interventions are still needed. Self-monitoring with or without daily symptom diary, telemonitoring, frequent telephone calls by case managers, or other technologies such as interactive voice response may all play a role in alerting both patients and the health care team to the development of an exacerbation. Future studies are needed to help understand the role of different symptom and physiologic monitoring approaches in care management in order to correctly identify COPD exacerbations, assess need for evaluation by the health care team, and initiate appropriate and prompt treatment and follow-up care

References:

1. Fan VS, Gaziano JM, Lew R, et al. A comprehensive care management program to prevent chronic obstructive pulmonary disease hospitalizations: a randomized, controlled trial. Ann Intern Med. May 15 2012;156(10):673-683.

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Summary for Patients

A Comprehensive Care Management Program to Prevent Chronic Obstructive Pulmonary Disease Hospitalizations

The full report is titled “A Comprehensive Care Management Program to Prevent Chronic Obstructive Pulmonary Disease Hospitalizations. A Randomized, Controlled Trial.” It is in the 15 May 2012 issue of Annals of Internal Medicine (volume 156, pages 673-683). The authors are V.S. Fan, J.M. Gaziano, R. Lew, J. Bourbeau, S.G. Adams, S. Leatherman, S.S. Thwin, G.D. Huang, R. Robbins, P.S. Sriram, A. Sharafkhaneh, M.J. Mador, G. Sarosi, R.J. Panos, P. Rastogi, T.H. Wagner, S.A. Mazzuca, C. Shannon, C. Colling, M.H. Liang, J.K. Stoller, L. Fiore, and D.E. Niewoehner.

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