Communicating With Your Patients About the Risks of Therapies

Meenakshi Bewtra, MD MPHUniversity of Pennsylvania

Division of GastroenterologyCenter for Clinical Epidemiology &

Biostatistics

CCEB

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

Outline:

• Risks of immunosuppressant therapy• Benefits of immunosuppressant therapy• Putting it all together: for the physician• Putting it all together: for the patient• Conclusion

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

Disclaimer

All risks estimates are approximations based upon calculations of available data

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)

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)

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)

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

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)

Outline:

• Risks of immunosuppressant therapy• Benefits of immunosuppressant therapy• Putting it all together: for the physician• Putting it all together: for the patient• Conclusion

Risk of medication cessation:• Azathioprine

Trenton X et al. Clin Gastroenterol Hepatol 2009;7:80-5

Risk of medication cessation:

• InfliximabIntra-abdominal surgeries CD-related hospitalizations

Rutgeerts P et al. Gastroenterology 2004;126(2):402

Risk of medication cessation:• Cessation of anti-TNF therapy when on

combination therapy

Louis E et al. Gastroenterology 2012;142(1):63-70

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

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;125:320Lichtenstein et al Clin Gastro Hep 2006;4:621Toruner et al. Gastro 2008;134:929-36

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;4:621–630Lewis et al. Am J Gastro 2008;103:1428–1435

Untreated/Active IBD: risk of mortality

Lewis et al. Am J Gastro 2008;103:1428–1435

Outline:

• Risks of immunosuppressant therapy• Benefits of immunosuppressant therapy• Putting it all together: for YOU• Putting it all together: for the patient• Conclusion

How do these risks stack up?*Immunosuppressant

therapyCorticosteroids /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 death 146 (steroids)

Number needed not to treat to cause one additional death 21 (active disease)

Adapted from: Lewis JD et al, Am J Gastro 2008 Lichtenstein G et al. CGH 2006Kandiel A et al. Gut 2005 Siegel C. et al. CGH 2006 Herrinton L et al Pharm Drug Safe 2012Trenton X et al. CGH 2009 Rutgeerts P et al. Gastro 2004 Singh S et al, IBD 2012Toruner M et al, Gastro 2008 Grijalva CG et al, JAMA 2011 Bloomgren G et al NEJM 2012

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”

Outline:

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

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 2004Aptar AJ et al, J Gen Intern Med 2008Renya VF et al, Individ Differ 2008Fagerlin A et al, Med Decis Making 2007

• 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 2004Aptar AJ et al, J Gen Intern Med 2008Fagerlin A et al, Med Decis Making 2007

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 2004 Reyna VF et al Learn Individ Diff 2008Akl EA et al Cochrane Database Syst Rev 2011 Brase GL J Behav Decis Making 2002Fagerlin A et al Am J Health Beahv 2007 Garcia-Retamero Am J Pub Health 2009Ancker JS et al, J Am Med Inform Assoc 2006 Yamagishi K. Appl Cogn Psychol 1997

Discussing risk with patients• Use visual aids!

Outline:

• Risks of immunosuppressant therapy• Benefits of immunosuppressant therapy• Putting it all together: for YOU• Putting it all together: for the patient• Conclusion

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

Thank you!