1. How Do We Individualize Guidelines in an Era of Personalized Medicine? Douglas K. Owens, MD, MS VA Palo Alto Health Care System Stanford University, Stanford CA, USA September 2016 Credit: The White House

2. 2 Disclosures and Disclaimer No financial disclosures Chair, American College of Physicians Guideline Group Member, U.S. Preventive Service Task Force 2012-2015 Disclaimer: Views mine, not USPSTF or US Government

3. Things we know about someone Age Comorbidities Gender Preferences Genomic data Change Risk Modify response to intervention Modify disease course Individualizing Guidelines

4. Intervention Health Outcomes (length and quality of life) Evidence Intermediate Outcomes Lung cancer: National Lung Screening Trial HIV screening Statins: Primary prevention trials

5. Goal: Determine Net Benefit Benefit Harms Age Comorbidities Gender Preferences Genomic data

6. 6 Examples from the U.S. Preventive Services Task Force Aspirin for prevention of CVD and colorectal cancer Statins for CVD prevention

7. 7 USPSTF Members The 16 volunteer members represent disciplines of primary care including family medicine, internal medicine, nursing, obstetrics and gynecology, pediatrics, and behavioral medicine Led by a Chair and Vice Chairs Serve 4-year terms Appointed by AHRQ Director with guidance from Chair and Vice Chairs Current members include deans, medical directors, chief health officers, practicing clinicians, and professors

8. 8 The USPSTF Makes recommendations on clinical preventive services to primary care clinicians – screening tests – counseling – preventive medications Affordable Care Act requires insurers to cover without co-pay any services rated as A or B (recommended) by USPSTF

10. 10 Evidence review supports effectiveness and harms of aspirin 22% reduction in non-fatal myocardial infarction 14% reduction in non-fatal stroke 33% reduction in mortality of colorectal cancer at 20 years 58% increase in gastrointestinal bleeding 27% increase in intracranial bleeding

11. Goal: Determine Net Benefit of Aspirin Benefit Harms Age Comorbidities Gender Preferences Genomic data nonfatal MI, stroke, CRC GI, intracranial bleeds

12. 12 Balance of benefit and harms depends on absolute risks (not relative risks) Greater absolute risk of CVD means greater benefit from aspirin Risk of CVD depends on age, gender, and comorbidities USPSTF recommended use of the ACC/AHA pooled risk equation to estimate CVD risk

13. ACC/AHA pooled risk equation for predicting 10-year CVD risk

14. 14 No similar risk estimator for bleeding risk Risk of bleeding depends on: » Aspirin dose and duration » History of GI ulcers or abdominal pain » Renal failure, severe liver disease, thrombocytopenia, bleeding disorders, diabetes » Other medications, including NSAIDs and anticoagulants » Male sex, OLDER AGE, current smoker, uncontrolled hypertension

15. Goal: Determine Net Benefit of Aspirin Benefit Harms Age Comorbidities Gender Preferences Genomic data nonfatal MI, stroke, CRC GI, intracranial bleeds

16. 16 How did we balance these complex benefits and harms and allow for individualization? Decision model to estimate: » Benefits: MI, stroke, cancer averted » Harms: GI bleeds, intracranial bleeds » Life years gained (or lost) » Quality-adjusted life years gained (or lost) » Effect of patient preferences (that is, judgements about quality of life with health outcomes and medication)

18. Estimated health outcomes from use of aspirin Bibbins-Domingo et al, USPSTF. Ann Intern Med 2016: 164(12):836-45

19. Goal: Determine Net Benefit of Aspirin Benefit Harms Age Comorbidities Gender Preferences Genomic data nonfatal MI, stroke, CRC GI, intracranial bleeds

20. USPSTF Recommendation – initiate aspirin if: 50 to 59 » > 10% 10 year CV risk » NO increased bleeding risk » life expectancy of at least 10 years » willing to take aspirin for 10 years (grade = B) 60 to 69 » same criteria » and patient places higher value on potential benefits than harms (grade = C) Bibbins-Domingo et al, USPSTF. Ann Intern Med 2016: 164(12):836-45

22. 22 USPSTF (draft) recommends statin if: 40 to 75 years » > 10% 10-year CVD risk AND » One or more of the following risk factors: – Hypertension – Dyslipidemia – Diabetes – Smoking – B recommendation

23. 23 Data is not always available to individualize Black women have higher death rate from breast cancer (USPSTF Screening for breast cancer. Ann Intern Med 2016 164: 279-296.) Black race is associated with higher incidence and mortality from colorectal cancer (USPSTF CRC screening JAMA. 2016;315(23):2564-2575) Black men have increased risk of developing and dying of prostate cancer (USPSTF Prostate cancer screening. Ann Intern Med. 2012;157:120- 134) Aspirin use in people over 75

24. How to individualize guidelines in an era of personalized/precision medicine? Credit: www.whitehouse.gov

25. Conclusion: Feasible to individualize guidelines Requires evidence linking personal characteristics to » Risk » Disease course » Different treatment response Decide what standard of evidence is required » How much extrapolation is reasonable? Modeling can be very useful, may be essential » But is limited by data also » Is modeling sufficient?

26. Thanks