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ADHD drugs and CV outcomes: Preliminary feasibility study results

ADHD drugs and CV outcomes: Preliminary feasibility study results. David J. Graham, MD, MPH on behalf of the FDA Epidemiology Contracts Study Team DSARM Advisory Committee Meeting February 9, 2006. FDA’s Epidemiology Contracts Program. Replaces Cooperative Agreement Program

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ADHD drugs and CV outcomes: Preliminary feasibility study results

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  1. ADHD drugs and CV outcomes: Preliminary feasibility study results David J. Graham, MD, MPH on behalf of the FDA Epidemiology Contracts Study Team DSARM Advisory Committee Meeting February 9, 2006

  2. FDA’s Epidemiology Contracts Program • Replaces Cooperative Agreement Program • Provides capability to study safety questions in a population setting and to collaborate with non-govt experts • 4 awardees Covered lives • HMO Research Network 3.2 million • Ingenix (i3 Drug Safety) 12 million • Kaiser Permanente Research Institute 6.1 million • TN and WA Medicaid 2.2 million • Turnover: 1 yr: 8%-30%; 5 yrs: 25%-80% • Funding • 2005-06 $1.6 million • 2006-07 $0.9 million

  3. Feasibility study design • Inception cohorts, all ages • Study period • Jan 1998-June 2005 (i3, KPRI, Medicaid) • July 2000-June 2005 (HMO RN) • Drugs of interest • Amphetamine or dextroamphetamine • Methylphenidate • Atomoxetine • Age-groups • Children/adolescents (1-19 years) • Adults (20-64 years) • Outcomes of interest • Sudden unexplained death • Acute myocardial infarction • Other ischemic heart disease • Cerebrovascular accident • Arrhythmia • Hypertension • Pulmonary hypertension

  4. Base population characteristics over study period

  5. Number of patients treated with ADHD drugs by age-group

  6. Person-years (crude) of ADHD drug use by age-group

  7. ADHD drug use (% males) by age-group

  8. Persistency of ADHD drug use by drug in 0-19 year olds Methylphenidate Amphetamine Atomoxetine

  9. Persistency of ADHD drug use by drug in 20+ year olds Methylphenidate Amphetamine Atomoxetine

  10. Cardiovascular outcomes of interest:Estimated population background rates • Sudden unexplained death • Children/adolescents: 1-9 per 105 pyrs • Adults: Age 20-64: 45 per 105 pyrs • Age 65+: 700 per 105 pyrs • Acute myocardial infarction • Children/adolescents: 10-20 per 105 pyrs • Adults: Age 20-64: 200 per 105 pyrs • Age 65+: 1700 per 105 pyrs • Stroke (all types) • Children/adolescents: 3 per 105 pyrs • Adults: Age 20-64: 150 per 105 pyrs • Age 65+: 1200 per 105 pyrs Sources: Heart disease and stroke statistics- 2004 update. American Heart Association; US census data, 2000

  11. Counts of potential study outcomes within inception cohorts,based on 1 hospital discharge diagnoses AMI: acute myocardial infarction IHD: ischemic heart diseas CVA: cerebrovascular accident (stroke) HTN: hypertension

  12. All cause mortality reported within inception cohorts • Deaths occurred at any time after cohort entry • From any cause • In-hospital only from 2 sites, not reported from 1 site • Sudden out of hospital deaths included from 1 site • 2 sites have death certificate linkage; SCD validated at 1 • NDI search required with other 2 sites - turnover, time, $$ • Total deaths substantially underestimated

  13. Crude frequency of diagnoses that could increase the risk of cardiovascular outcomes in ADHD drug treated patients

  14. Power to identify a given risk ratio with abackground rate = 15 per 105 person-years(AMI in children 1-19 years) RR=5 1.00 0.80 RR=3 0.60 Power (1-beta) RR=2 0.40 0.20 0.00 40 80 120 160 200 240 280 320 360 400 Exposure cohort person-years (thousands)

  15. Power to identify a given risk ratio with abackground rate = 3 per 105 person-years(CVA in children 1-19 years) 1.00 RR=10 0.80 RR=5 0.60 Power (1-beta) RR=3 0.40 0.20 RR=2 0.00 40 80 120 160 200 240 280 320 360 400 Exposure cohort person-years (thousands)

  16. Power to identify a given risk ratio with a background rate = 200 per 105 person-years (AMI and CVA in adults 20-64 years) RR=3 1.00 0.80 RR=2 0.60 Power (1-beta) 0.40 RR=1.5 0.20 0.00 0 20 40 60 80 100 Exposed cohort person-years (thousands)

  17. Probability of excluding a given risk ratio, assuming true RR=1: background = 15 per 105 person-years(AMI in children age 1-19) RR=2 RR=3 RR=5▲

  18. Probability of excluding a given risk ratio, assumingtrue RR=1: background = 3 per 105 person-years(CVA in children age 1-19) RR=2  RR=3  RR=5 ▲ RR=10 ●

  19. Probability of excluding a given risk ratio, assumingtrue RR=1: background = 200 per 105 person-years(AMI or CVA in adults age 20-64) RR=2  RR=3 

  20. Estimated risk ratio that might be detected with  80% probability by age- and drug-group AMI: acute myocardial infarction CVA: cerebrovascular accident (stroke)

  21. Some additional power considerations AMI: acute myocardial infarction CVA: cerebrovascular accident (stroke)

  22. Caveats • Preliminary results • Crude definitions of exposure, outcome • Hospital D/C diagnoses, not validated • Outcome post 1st Rx; relation to current use not known • Out of hospital deaths (SCD) captured at only 1 site • Comorbidities broadly defined • Could shift with refinement during in-depth study • Relationship to outcomes with respect to age not known • Power calculations crude • Some uncertainty regarding background rates

  23. Summary • Potential for CV risk with ADHD drugs • High prevalence of use in children; growing in adults • Sudden unexplained death of 1 interest; most difficult to study • TN Medicaid and KPRI have death certificate linkage • TN data can go back ~20 years; KPRI ~8 years • Other sites would require NDI search • Other CV outcomes • Feasibility study • Exposed person-time substantial for most ADHD drugs • CV outcomes require validation; timing with respect to exposure • Power probably sufficient to address several outcomes • Number of arrhythmia cases seems surprisingly high

  24. FDA Epidemiology Contracts ADHD Study Team (listed by site) • FDA, ODS • Kate Gelperin, MD, MPH • Andrew Mosholder, MD, MPH • David J. Graham, MD, MPH • Judy A. Staffa, PhD • HMO Research Network • Susan E. Andrade, PhD • Ingenix (i3 Drug Safety) • K. Arnold Chan, MD, ScD • Kaiser Permanente Research Institute • Joe Selby, MD, MPH • Medicaid (TN and WA) • William Cooper, MD, MPH

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