Evidence-based management of apnea of prematurity: Is caffeine the - PowerPoint PPT Presentation

Barbara Schmidt, MD, MSc, CM Evidence-based management of apnea of prematurity: Is caffeine the magic bullet?

B Adams K Barrington P Davis A Golan E Goldsch E Herlenius C Mayes A Ohlsson K Sankaran A Solimano Caffeine for Apnea of Prematurity (CAP) R. Alvaro J Dix N Granke M Lacy D Moddemann R Sauve A Synnes Trial P Anderson K Callanan D Dewey H Halliday H Lagercrantz T Mulder R Regev B Schmidt W Tin S Arnon M Clarke L Doyle AM Hamiltion A Juster-Reicher B Lemyre K O’Brien G Reynolds A Schulze H Walti H-U Bucher L Costantini A Golan R Haslam M Khairy H MacLean G Opie R Roberts E Shinwell A van Wassenaer

CAP Trial Timeline 1998 Formulation of study question 1999-2004 Enrolment of > 2000 infants 2006 Short-term outcomes 2007 Primary outcome at 18 months 2008 Inaugural Trial of the Year Award 2012 Outcomes at 5 years 2017 Outcomes at 11 years

ORIGINAL STUDY QUESTION Among infants with BW 500-1250 g P who are at risk of apnea of prematurity, does the use of caffeine I compared with placebo C O increase the risk of death or neurosensory disability T at a corrected age of 18 months

PATIENT ACCRUAL Europe Canada/US n=434 n=1052 Australia n=520

Short Term Outcomes of the Caffeine Trial Caffeine Placebo Odds Ratio Outcome n/N n/N (95% CI) BPD 350/963 447/954 Severe ROP 49/965 75/955* Brain injury 126/967 138/966 NEC 63/1006 67/1000 PDA drug Tx 293/1001 381/999 PDA surgery 45/1001 126/999 0.2 0.5 1 2 5 NEJM 2006;354:2112 and *2007;357:1893 Favours Caffeine Favours Placebo

18-Months Outcomes of the Caffeine Trial Caffeine Placebo Odds Ratio Outcome n/N n/N (95% CI) Death or disability 377/937 431/932 Death 62/974 63/970 Cerebral Palsy 40/909 66/901 Cognitive delay 293/867 329/858 Hearing loss 17/909 22/905 Blindness 6/911 8/905 0.2 0.5 1 2 5 N Engl J Med 2007;357:1893 Favours Caffeine Favours Placebo

2008 SCT/Imp /ImpACT ACT CLINI INICAL CAL TRIAL AL OF THE YEAR R A W ARD Long Term Effects of Caffeine for Apnea of Prematurity Trial PI: Barbara Schmidt, MD, MSc In recognition of a landmark randomized clinical trial to improve the lives of premature infants. Eleanor McFadden, MA Steven Goodman, MD, PhD President, Society for Clinical Trials Project ImpACT

Death or Disability at 5 Years Caffeine Placebo 200 of 807 176 of 833 24.8% 21.1% OR = 0.82 95% CI 0.65-1.03 p = 0.09

Gross Motor Function (GMFCS) Level Caffeine Placebo P-value Normal 91% 86% 0.006 1 7.0% 10.1% 2 0.7% 1.0% 3 0.6% 0.6% 4 0.5% 1.3% 5 0.5% 0.8%

Rates of DCD at 5 Years Caffeine Placebo 106 of 698 83 of 735 15.2% 11.3% OR = 0.70 95% CI 0.51-0.95 p =.024

Study Question Among English or French speaking P CAP trial participants, I does neonatal caffeine therapy C compared with placebo decrease the risk of functional O impairment T at age 11 years?

Primary Outcome at 11 Years Functional impairment-at least 1 of: • Poor academic performance • Motor Impairment • Behavior Problem Tests: Wide Range Achievement Test-4 Movement ABC-2 Child Behavior Checklist - Parent

1202 CAP children were eligible 602 caffeine 600 placebo 457 463 (76%) (77%) Composite Primary Outcome

Outcomes of 11 Year Cohort at 18 Mo Caffeine Placebo P-value Disability 29.7% 36.4% 0.03 CP 3.8% 7.0% 0.03 MDI < 85 27.8% 31.3% 0.25 MDI < 70 9.7% 12.3% 0.22

Functional Impairment at 11 Years Caffeine Placebo 174 of 463 145 of 457 37.6% 31.7% OR = 0.78 95% CI 0.59-1.02 p = 0.07

Types of Impairments Caffeine Placebo P-value Academic 14.4% 13.2% 0.58 Motor 19.7% 27.5% 0.009 Behavior 10.9% 8.3% 0.22

Types of Impairments Caffeine Placebo P-value Academic 14.4% 13.2% 0.58 Motor 19.7% 27.5% 0.009 Behavior 10.9% 8.3% 0.22 Number Needed to Treat: 13 (95% CI, 8 to 42)

Conclusion I Caffeine therapy for apnea of prematurity did not significantly reduce the combined rate of academic, motor and behavioral impairments at age 11 years. However,

Conclusion II Caffeine therapy reduced the risk of motor impairment 11 years later. At the doses used in the CAP trial, neonatal caffeine therapy is effective and safe into middle school age.

Last Use of Respiratory Support* Caffeine Placebo P value Intubation 29.1 30.0 <0.0001 Any pos. 31.0 32.0 <0.0001 pressure Oxygen 33.6 35.1 <0.0001 * Median Postmenstrual Age

Explaining the benefit of caffeine PMA at last use of any positive airway pressure (mean, 31.4 weeks caffeine; 32.8 weeks placebo) explained 53% (95% CI, 22-100%) of the benefit of caffeine on motor impairment 11 years later.

Explaining the benefit of caffeine “Caffeine likely is not a direct brain or a lung drug but rather a drug that decreases adverse effects of interventions to treat apnea”. Alan Jobe, AJRCCM 2017

PEDIATRICS 2016: 137;e20

AAP Conclusion Caffeine citrate is a safe and effective treatment of apnea of prematurity when administered at • 20 mg/kg loading dose • 5 to 10 mg/kg per day maintenance

Beware of risky treatment creep 1. Indication: Apnea of prematurity 2. Dose: More is not always better 3. Timing: How early is too early? In the CAP trial, the median age at start of drug therapy was 3 days.

CAP Children + Families Neonatal Trials Group McMaster University Investigators + staff in Canada Australia United Kingdom Sweden Canadian Institutes of Health Research (CIHR)