1. Communicating With Your Patients About the Risks of Therapies Meenakshi Bewtra, MD MPH University of Pennsylvania Division of Gastroenterology Center for Clinical Epidemiology & Biostatistics CCEB

2. Outline: Risks of immunosuppressant therapy* Benefits of immunosuppressant therapy* Putting it all together: for the physician Putting it all together: for the patient Conclusion Immunosuppressant therapy: thiopurine analogs, biologics, calcineurin inhibitors, methotrexate

3. Outline: Risks of immunosuppressant therapy Benefits of immunosuppressant therapy Putting it all together: for the physician Putting it all together: for the patient Conclusion

4. Risks in Immunosuppressant Therapy* Serious/Opportunistic Infections Lymphoma Hepatosplenic T-Cell Lymphoma (HSTCL) Progressive Multifocal Leukoencepholapthy (PML) *All following risks estimates are approximations based upon (my) calculations of available data

5. Disclaimer All risks estimates are approximations based upon calculations of available data

6. Risks in Immunosuppressant Therapy Serious/Opportunistic Infections – 3% / year risk monotherapy – 5% / year with combination therapy Lymphoma Hepatosplenic T-Cell Lymphoma (HSTCL) Progressive Multifocal Leukoencepholapthy (PML)

7. Risks in Immunosuppressant Therapy Serious/Opportunistic Infections – 3% / year risk monotherapy – 5% / year with combination therapy Lymphoma – 4x increased risk (monotherapy) – 8x increased risk (combination) Hepatosplenic T-Cell Lymphoma (HSTCL) Progressive Multifocal Leukoencepholapthy (PML)

8. Risks in Immunosuppressant Therapy Serious/Opportunistic Infections – 3% / year risk monotherapy – 5% / year with combination therapy Lymphoma – 4x increased risk (monotherapy) – 8x increased risk (combination) Hepatosplenic T-Cell Lymphoma (HSTCL) – 160x increased risk Progressive Multifocal Leukoencepholapthy (PML)

9. Risks in Immunosuppressant Therapy Serious/Opportunistic Infections – 3% / year risk monotherapy – 5% / year with combination therapy Lymphoma – 4x increased risk (monotherapy) – 8x increased risk (combination) Hepatosplenic T-Cell Lymphoma (HSTCL) – 160x increased risk Progressive Multifocal Leukoencepholapthy (PML) – 1 out of every 7000 treated; infinitely increased risk

10. Risks in Immunosuppressant Therapy Serious/Opportunistic Infections – 30/1000 annual risk (monotherapy) – 50/ 1000 annual risk (combination therapy) Lymphoma – 0.8/1000 annual incidence (monotherapy) – 1.6/1000 annual incidence (combination) Hepatosplenic T-Cell Lymphoma (HSTCL) – 0.0034 /1000 annual incidence Progressive Multifocal Leukoencepholapthy (PML) – 0.14/1000 (not necessarily annual incidence)

11. Outline: Risks of immunosuppressant therapy Benefits of immunosuppressant therapy Putting it all together: for the physician Putting it all together: for the patient Conclusion

12. Risk of medication cessation: Azathioprine Trenton X et al. Clin Gastroenterol Hepatol 2009;7:80-5

13. Risk of medication cessation: Infliximab Intra-abdominal surgeriesCD-related hospitalizations Rutgeerts P et al. Gastroenterology 2004;126(2):402

14. Risk of medication cessation: Cessation of anti-TNF therapy when on combination therapy Louis E et al. Gastroenterology 2012;142(1):63-70

15. Corticosteroids: are bad Fluid retention CHF Metabolic abnormalities Hypertension Muscle weakness Loss of muscle mass Osteoporosis Compression fractures (spine) Aspectic necrosis (femoral/humeral head) Pathologic fractures Tendon rupture Hyperglycemia cataracts Gastric ulcers Pancreatitis Impaired wound healing Bruising Pseudotumor cerebri Emotional disturbances Menstrual irregularities Cushingoid features Growth suppression (children) Secondary adrenocortical /pituitary unresponsiveness Diabetes mellitus Glaucoma Weight gain

16. Corticosteroids: Infection risk Serious infections: TREAT registry – Adj OR 2.2 (1.5-3.3), p=0.001 Opportunistic infection: Mayo Clinic – OR 3.3 (1.8-6.1), p<0.001 Post-operative infections: elective IBD surgery – Any infection (29%): OR 3.7 (1.2-11.0) – Major infection (20%):OR 5.5 (1.1-27.3) Higher risk with higher dosages used Aberra et al. Gastro 2003;125:320 Lichtenstein et al Clin Gastro Hep 2006;4:621 Toruner et al. Gastro 2008;134:929-36

17. Corticosteroids: risk of mortality Lichtenstein: TREAT – Corticosteroid use: OR 2.1 (1.1–3.8) p=.016 Lewis: GPRD Lichtenstein et al. Clin Gastro Hep 2006;4:621–630 Lewis et al. Am J Gastro 2008;103:1428–1435

18. Untreated/Active IBD: risk of mortality Lewis et al. Am J Gastro 2008;103:1428–1435

19. Outline: Risks of immunosuppressant therapy Benefits of immunosuppressant therapy Putting it all together: for YOU Putting it all together: for the patient Conclusion

20. How do these risks stack up?* Immunosuppressant therapy Corticosteroids /Active Disease Number needed to treat to cause one additional serious infection per year with therapy 483 (monotherapy) 276 (combo therapy) 483 (steroids) Number needed to treat to cause one additional lymphoma per year with therapy 4357 (age 20-29; AZA) 355 (age > 65; AZA) 2380 (infliximab) 714 (combo therapy) Number needed to treat to cause one additional HSTCL per year with therapy 20,964 Number needed to treat to cause one additional PML per year with therapy 7,000 Number needed to cause one additional relapse per year by stopping therapy (azathioprine) 3 Number needed to cause one additional hospitalization per year with episodic therapy (infliximab) 7 Number needed to cause one additional abdominal surgery per year with episodic therapy (infliximab) 21 Number needed to treat to cause one additional death146 (steroids) Number needed not to treat to cause one additional death21 (active disease) Adapted from:Lewis JD et al, Am J Gastro 2008Lichtenstein G et al. CGH 2006 Kandiel A et al. Gut 2005 Siegel C. et al. CGH 2006Herrinton L et al Pharm Drug Safe 2012 Trenton X et al. CGH 2009 Rutgeerts P et al. Gastro 2004Singh S et al, IBD 2012 Toruner M et al, Gastro 2008Grijalva CG et al, JAMA 2011Bloomgren G et al NEJM 2012

21. Why is changing the way we practice so hard? How one perceives risk: – Epidemiologist: risk is a measured property of a group of people – Physician/patient: risk is a specific property of ME Perception becomes reality: – Reject statistical reasoning in favor of anecdotal reasoning – Accept common risks we “know” in favor of uncommon risks we “fear”

22. Outline: Risks of immunosuppressant therapy Benefits of immunosuppressant therapy Putting it all together: for the physician Putting it all together: for your patient Conclusion

23. Discussing risk with patients Numeracy: basic math skills for health-related activities – Over 50% of Americans lack minimum basic skills to apply to arithmetic operations of numbers in print materials Patients have problems with risk presentation, framing, proportions/probabilities, denominator neglect Burkell J et al, J Med Libr Assoc 2004 Aptar AJ et al, J Gen Intern Med 2008 Renya VF et al, Individ Differ 2008 Fagerlin A et al, Med Decis Making 2007

24. Risk presentation: – Avoid vague labels such as “low,” “very low,” “often” or “very common” which lead to inconsistent interpretations Framing – Relative risks can make small (rare) risks appear large (infinite) Absolute risks anchor all risks – Use similar frame (“gain frame” or “loss frame”) Discussing risk with patients Burkell J et al, J Med Libr Assoc 2004 Aptar AJ et al, J Gen Intern Med 2008 Fagerlin A et al, Med Decis Making 2007

25. Discussing risk with patients Avoid “artificial” constructs such as proportions, ratios, probabilities, odds – Require conditional math skills – Use frequencies/count data Denominator neglect: people are very sensitive to numerators Ex: 1,286 in 10,000 viewed riskier than 24 in 100 – Present all risks with similar denominator Burkell J et al, J Med Libr Assoc 2004Reyna VF et al Learn Individ Diff 2008 Akl EA et al Cochrane Database Syst Rev 2011Brase GL J Behav Decis Making 2002 Fagerlin A et al Am J Health Beahv 2007Garcia-Retamero Am J Pub Health 2009 Ancker JS et al, J Am Med Inform Assoc 2006Yamagishi K. Appl Cogn Psychol 1997

26. Discussing risk with patients Use visual aids!

27. Outline: Risks of immunosuppressant therapy Benefits of immunosuppressant therapy Putting it all together: for YOU Putting it all together: for the patient Conclusion

28. Conclusions: There are documented risks with immunosuppressant therapy – The absolute risks are low – Did not discuss: higher-risk populations (elderly, young men) The absolute risks of active/untreated disease and/or corticosteroid therapy are high Be aware of numeracy issues when discussing with patients – Avoid vague descriptions of risk, use absolute counts with similar denominators, and consider incorporating visual aids

29. Thank you!