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Mortality Associated With Medical Therapy Versus Elective Colectomy in Ulcerative Colitis: A Cohort StudyMortality Associated With Medical Therapy Versus Elective Colectomy in UC

Meenakshi Bewtra, MD, MPH, PhD; Craig W. Newcomb, MS; Qufei Wu, MS; Lang Chen, PhD; Fenglong Xie, MS; Jason A. Roy, PhD; Cary B. Aarons, MD; Mark T. Osterman, MD, MSCE; Kimberly A. Forde, MD, MHS; Jeffrey R. Curtis, MD, MS, MPH; and James D. Lewis, MD, MSCE
[+] Article, Author, and Disclosure Information

This article was published online first at www.annals.org on 14 July 2015.


From University of Pennsylvania, Philadelphia, Pennsylvania, and University of Alabama at Birmingham, Birmingham, Alabama.

Acknowledgment: The authors thank Samy Suissa, PhD, for technical input on the study design.

Grant Support: By the National Institutes of Health (K08 DK084347-01 and K24 DK078228) and the Agency for Healthcare Research and Quality (R01HS018517).

Disclosures: Dr. Bewtra reports a grant from the National Institutes of Health during the conduct of the study and speaking engagements for Imedex and the Crohn's & Colitis Foundation of America/Robert Michael Educational Institute outside the submitted work. Dr. Osterman reports personal fees from Janssen Pharmaceuticals and Takeda Pharmaceutical Company and a grant from UCB outside the submitted work. Dr. Curtis reports grants and personal fees from Roche/Genentech, UCB, Janssen Pharmaceuticals, CORRONA, Amgen, Pfizer, Bristol-Myers Squibb, Crescendo Pharmaceuticals, and AbbVie outside the submitted work. Dr. Lewis reports a grant from the National Institutes of Health during the conduct of the study; grants from Takeda Pharmaceutical Company, Shire, Nestlé Health Science, and Centocor outside the submitted work; and personal fees from Takeda Pharmaceutical Company, Shire, Nestlé Health Science, Janssen Pharmaceuticals, AbbVie, Immune Pharmaceuticals, AstraZeneca, Amgen, MedImmune, Pfizer, and Merck outside the submitted work. Authors not named here have disclosed no conflicts of interest. Disclosures can also be viewed at www.acponline.org/authors/icmje/ConflictOfInterestForms.do?msNum=M14-0960.

Editors' Disclosures: Christine Laine, MD, MPH, Editor in Chief, reports that she has no financial relationships or interests to disclose. Darren B. Taichman, MD, PhD, Executive Deputy Editor, reports that he has no financial relationships or interests to disclose. Cynthia D. Mulrow, MD, MSc, Senior Deputy Editor, reports that she has no relationships or interests to disclose. Deborah Cotton, MD, MPH, Deputy Editor, reports that she has no financial relationships or interest to disclose. Jaya K. Rao, MD, MHS, Deputy Editor, reports that she has stock holdings/options in Eli Lilly and Pfizer. Sankey V. Williams, MD, Deputy Editor, reports that he has no financial relationships or interests to disclose. Catharine B. Stack, PhD, MS, Deputy Editor for Statistics, reports that she has stock holdings in Pfizer.

Reproducible Research Statement:Study protocol: Available from Dr. Bewtra (e-mail, mbewtra@upenn.edu). Statistical code: Available from Mr. Newcomb (e-mail, cnewcomb@mail.med.upenn.edu). Data set: Patient-level data are not available. Research-identifiable data files are available to approved investigators through the Centers for Medicare & Medicaid Services.

Requests for Single Reprints: Meenakshi Bewtra, MD, MPH, PhD, Department of Gastroenterology, University of Pennsylvania, 724 Blockley Hall, 423 Guardian Drive, Philadelphia, PA 19104; e-mail, mbewtra@upenn.edu.

Current Author Addresses: Dr. Bewtra: Department of Gastroenterology, University of Pennsylvania, 724 Blockley Hall, 423 Guardian Drive, Philadelphia, PA 19104.

Mr. Newcomb: Center for Clinical Epidemiology and Biostatistics, University of Pennsylvania, 521 Blockley Hall, 423 Guardian Drive, Philadelphia, PA 19104.

Mr. Wu: Center for Clinical Epidemiology and Biostatistics, University of Pennsylvania, 515 Blockley Hall, 423 Guardian Drive, Philadelphia, PA 19104.

Dr. Chen: Division of Clinical Immunology and Rheumatology, University of Alabama at Birmingham, 1720 Second Avenue South, FOT 802C, Birmingham, AL 35294.

Mr. Xie: Division of Clinical Immunology and Rheumatology, University of Alabama at Birmingham, 520 20th Street South, FOT 802B, Birmingham, AL 35294.

Dr. Roy: Center for Clinical Epidemiology and Biostatistics, University of Pennsylvania, 629 Blockley Hall, 423 Guardian Drive, Philadelphia, PA 19104.

Dr. Aarons: Hospital of the University of Pennsylvania, 3400 Spruce Street, 4 Silverstein, Philadelphia, PA 19104.

Dr. Osterman: Penn Presbyterian Medical Center, Division of Gastroenterology, 51 North 39th Street, Philadelphia, PA 19104.

Dr. Forde: Department of Gastroenterology, University of Pennsylvania, 722 Blockley Hall, 423 Guardian Drive, Philadelphia, PA 19107.

Dr. Curtis: Division of Clinical Immunology and Rheumatology, University of Alabama at Birmingham, 510 20th Street South, FOT 802D, Birmingham, AL 35294.

Dr. Lewis: Department of Gastroenterology, University of Pennsylvania, 720 Blockley Hall, 423 Guardian Drive, Philadelphia, PA 19104.

Author Contributions: Conception and design: M. Bewtra, C.W. Newcomb, L. Chen, J.R. Curtis, J.D. Lewis.

Analysis and interpretation of the data: M. Bewtra, C.W. Newcomb, Q. Wu, L. Chen, M.T. Osterman, K.A. Forde, J.R. Curtis, J.D. Lewis.

Drafting of the article: M. Bewtra, C.W. Newcomb, J.A. Roy, J.R. Curtis.

Critical revision of the article for important intellectual content: M. Bewtra, C.W. Newcomb, J.A. Roy, C.B. Aarons, M.T. Osterman, J.D. Lewis.

Final approval of the article: M. Bewtra, C.W. Newcomb, Q. Wu, L. Chen, F. Xie, J.A. Roy, C.B. Aarons, M.T. Osterman, K.A. Forde, J.R. Curtis, J.D. Lewis.

Provision of study materials or patients: M. Bewtra.

Statistical expertise: C.W. Newcomb, L. Chen, F. Xie, J.A. Roy.

Obtaining of funding: M. Bewtra, J.D. Lewis.

Administrative, technical, or logistic support: M. Bewtra.

Collection and assembly of data: M. Bewtra, C.W. Newcomb, F. Xie.


Ann Intern Med. 2015;163(4):262-270. doi:10.7326/M14-0960
Text Size: A A A

Background: Ulcerative colitis (UC) can be treated with surgery or medications. Patients often must choose between long-term immunosuppressant therapy or total colectomy. Whether one of these treatment approaches has a mortality benefit is uncertain.

Objective: To determine whether patients with advanced UC treated with elective colectomy have improved survival compared with those treated with medical therapy.

Design: Retrospective matched cohort study.

Setting: Data from all 50 states for Medicaid beneficiaries (2000 to 2005), Medicare beneficiaries (2006 to 2011), and dual-eligible persons (2000 to 2011).

Patients: 830 patients with UC pursuing elective colectomy and 7541 matched patients with UC pursuing medical therapy.

Measurements: The primary outcome was time to death. Cox proportional hazards models were used to compare the survival of patients with advanced UC treated with elective colectomy or medical therapy. The models controlled for significant comorbid conditions through matched and adjusted analysis.

Results: The mortality rates associated with elective surgery and medical therapy were 34 and 54 deaths per 1000 person-years, respectively. Elective colectomy was associated with improved survival compared with long-term medical therapy (adjusted hazard ratio [HR], 0.67 [95% CI, 0.52 to 0.87]), although this result did not remain statistically significant in all sensitivity analyses. Post hoc analysis by age group showed improved survival with surgery in patients aged 50 years or older with advanced UC (HR, 0.60 [CI, 0.45 to 0.79]; P = 0.032 for age-by-treatment interaction).

Limitations: Retrospective nonrandomized analysis is subject to residual confounding. The source cohort was derived from different databases throughout the study. Sensitivity and secondary analyses had reduced statistical power.

Conclusion: Elective colectomy seemed to be associated with improved survival relative to medical therapy among patients aged 50 years or older with advanced UC.

Primary Funding Source: National Institutes of Health and Agency for Healthcare Research and Quality.

Figures

Grahic Jump Location
Figure 1.

Study flow diagram.

COPD = chronic obstructive pulmonary disease; CPT = Current Procedural Terminology; IBD = inflammatory bowel disease; ICD-9 = International Classification of Diseases, Ninth Revision; UC = ulcerative colitis.

Grahic Jump Location
Grahic Jump Location
Figure 2.

Cumulative incidence of death.

Cumulative incidence is shown by solid lines, and 95% CIs are indicated by dashed lines. Data used to generate the graph are provided in Table 3.

Grahic Jump Location

Tables

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Comments

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Comment
Posted on August 26, 2015
William B. Freedberg, M.D., Ph.D., FACP
Northampton, MA
Conflict of Interest: None Declared
M. Bewtra et al. Mortality Associated with Medical Therapy versus Elective Colectomy in Ulcerative Colitis. Annals of Internal Medicine 163 No. 4 19 August 2015 262-270.

and

David B. Sachar [Editorial] Ulcerative Colitis: Dead or Alive. . Annals of Internal Medicine 163 No. 4 19 August 2015 316

I am writing as a soon to be 73 year old internist who had elective ileostomy and colectomy surgery at age 16. Perhaps there are other members of the ACP and Annals readers with similar experiences similar , but after reading these 2 very well done pieces I wanted to speak out.

My surgery was scheduled electively after 4 years of unremitting ulcerative colitis complicated by hospitalizations, recurrent bleeding with symptomatic anemia requiring transfusions, and ongoing corticosteroid treatment [the choice at the time] with side effects. The “quality of life” burden of unpredictable severe diarrhea with painful cramping, bleeding and incontinence was high. I missed much school time, had poor exercise tolerance, weight loss, and endured dietary interventions which rarely made a difference, as well as all the psychosocial disadvantages of being a “sick kid”.

The decision for surgery was not undertaken lightly. I had finished my junior year with enough knowledge from high school science classes to know something of the anatomy and physiology involved. I was fortunate to have meaningful discussions with of the pros and cons of surgery with my doctors, parents and other relatives. Though my parents had to be the ones signing the paperwork, the decision to go ahead with surgery was ultimately my own.

Two months after surgery I had made it through the steepest part of the learning curve of learning to live with my ileostomy and had returned to school and was able to graduate with my classmates and to attend college the following year.

Some 13 months after surgery I was a college freshman, taking classes that laid the foundation for fifty years of involvement in science and medicine. I signed on to do Sunday night volunteer work in a local hospital emergency room, and worked as an orderly at the same hospital the next summer. After college I spent a decade in basic microbiology and biochemistry research before attending medical school on a National Health Service Corps scholarship that led to a 5 year community health center assignment following internal medicine residency. Since then I have been involved in office and hospital and nursing home medicine and teaching and been certified in Geriatrics as well as Hospice and Palliative care medicine.

Very importantly, having life preserving and improving elective surgery as a teenager not just allowed me to have a 50 year career in biological research, medicine and teaching, but has allowed me to have a very full life as a husband, father, and now grandfather.

I have no idea how many other ACP members and Annals readers have stories like mine to tell, but the research done by Dr. Bewtra and Dr. Sachar’s thoughtful editorial struck home and made me appreciate more than ever not only the fortunate outcome I had, but the debt survivors such as myself owe to the physicians and surgeons who have who have labored over the past decades to make progress in the knowledge and treatment of inflammatory bowel disease. I am very grateful.



For UC: Surgery vs Medical therapy (with immunosuppresives) ?
Posted on August 27, 2015
Neelesh Gupta
University College of Medical Sciences & GTB Hospital (University of Delhi) New Delhi, India
Conflict of Interest: None Declared
Dear Editor,
I peruse with interest the seminal article by Bewtra M et al.

The Paper is timely as improvement in the total mortality with any modality of treatment assumes special significance.

The Authors made every attempt to nullify the Effect of Confounding Variables as much
as possible. However, as this is a Retrospective Data, The Bias cannot be eliminated completely.

The Authors could have commented upon ASA (American Society of Anaesthesiologists) score of the patients undergoing surgery.
As Surgery is often offered to and accepted by relatively good-risk patients, thus relatively better outcome is an expected finding.

Moreover as the patients receiving immunosuppressive therapy (optimally treated) had a good response, so no difference in the morality could be seen even above 50 years of age.

Therefore, My Take-Home on the paper is: Patient with Severe Ulcerative Colitis receiving Immunosuppressive Therapy (if he/she can tolerate), Surgery offers no survival advantage, irrespective of the Age of the patient.However, Surgery could be considered to further improve the symptoms, if needed.
Data not justofying conclusions
Posted on September 2, 2015
Bharat Rattan, MD MPH
UCSF Fresno
Conflict of Interest: None Declared
Thank for this great article.

Few points to ponder.

1. It is a retrospective cohort and not randomized control study. The decision to undertake surgery is itself prone to selection bias due to various factors. Surgeons are inclined to not operate on patients deemed prognostically poor. This is pointed by the Nilesh very well.

2. Important information about teaching hospitals or community hospitals can greatly affect style of practice. AT sub group this could be useful. Poor payments for procedures can also influence delayed surgical undertaking.

3. The data is collected over 10 yrs and secular trends of treatment and post operative care could have changed. Though temporal matching has been done to mitigate its effect. I think with access to large numbers, matching on multiple was not required since confounders could have been dealt at the level of analysis. This alters natural disease distribution and even though the study is internally valid, its external validity can be compromised. This is a methods issue. It is not clear if diagnosis was picked from admission records or discharge summaries. Exclusion of cancer and lymphoma could be relevant since they are complications of Immune modulators ( though it also depends on duration of treatment.

4. The current guidelines undertake a trial of oral and systemic therapy for 1-2 weeks ( affects by surgeon), by choosing to exclude ED visit only the day before may not be reflective of true nature. ED visit in last few weeks can affect how you categories the procedure. It is not so straightforward to dichotomize options into elective and non elective since most of such procedures are semi-elective.

4. Use of blood thinners and cardiovascular status are extremely important and may have been better way to adjust for comorbidity than the scale used by author. If most patients die of heart attack/COPD ( lets assume) and we have excluded them, the conclusions can not be applied to general population. The editor has also pointed issues relating to private payers.

5. The choice of end points as mortality is interesting. The editor has put comments that quality of life is more important since direct mortality from the disease is very low. On the contrary, choosing surgery in younger people may make sense due to cumulative side effects of immune modulating drugs over decades. New treatments which can be self administered will also be game changers. It hard to tell a person in 30s to be affected by small mortality benefit when he/she is around 70 yrs.

6. In subgroup analysis, the confidence intervals of disease curves are not separated significantly. And more so in group that received Immune modulating treatment.

7. Finally the cost of care and societal impact has to be looked. The author did not make it clear that at what stage surgery be offered. The definition for the purpose of study is to have certain admissions, certain meds and ED visits etc. DO we mean to offer it early or still offer it at a later stage with same reasoning (mortality benefit) after medical therapy fails.

As others have pointed out, use of immune modulating agents should be given a trial before coming to surgery in advanced disease. This is a hard question to settle with this design but has to be looked with more studies, which importantly should include more clinically relevant end points addressing quality of life.

Regards,
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Summary for Patients

Mortality Associated With Medical Therapy in Ulcerative Colitis

The full report is titled “Mortality Associated With Medical Therapy Versus Elective Colectomy in Ulcerative Colitis. A Cohort Study.” It is in the 18 August 2015 issue of Annals of Internal Medicine (volume 163, pages 262-270). The authors are M. Bewtra, C.W. Newcomb, Q. Wu, L. Chen, F. Xie, J.A. Roy, C.B. Aarons, M.T. Osterman, K.A. Forde, J.R. Curtis, and J.D. Lewis.

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