The PINT Study Journal of Pediatrics Sept 2006;149:301-7

1. The PINT StudyJournal of Pediatrics Sept 2006;149:301-7 Yulia Lin, MD FRCPC Transfusion Medicine Resident, University of Toronto Transfusion Medicine Residents Journal Club January 24, 2007

2. Rationale • Extremely low birth weight infants (ELBW<1000g) account for 9% of NICU admissions • 94% received RBC transfusion (lab sampling and immature hematopoietic system) • Risks and benefits of transfusion unclear • Risks: transfusion-associated infections and iron overload • Benefits: avoiding morbidities associated with chronic anemic hypoxemia

3. Question • Population: ELBW newborn infants • Intervention: Transfusion algorithm • Restrictive Hb thresholds • Liberal Hb thresholds • Outcome: • Composite of death or survival with severe morbidity at time of discharge PICOT

4. Enrolled from 10 NICUs in Canada, US, Australia Inclusion ELBW < 1000g GA < 31 weeks < 48 hrs at enrollment Informed consent from parent/guardian Exclusion Transfusion after 6 hrs of age Deemed non-viable Cyanotic heart disease Acute shock Congenital anemia Family history of anemia or hemolytic disease Anticipated epo use Known parental opposition to transfusion Population

5. Intervention • Randomized to low (restrictive) or high (liberal) Hb threshold • Allocation done at coordinating centre • Stratified by center and birth weight

6. Intervention • Intervention • Transfusions: washed, packed RBCs 15ml/kg given within 6 hours of Hb value • Non-algorithm dictated RBC transfusions in event of shock, severe sepsis, coagulation defects, surgery or for unanticipated emergencies • Caregivers not blinded to algorithm • Did not dictate how often Hb measured

7. Patient Flow

8. Baseline characteristics Are the columns equal? Who is the typical pt? Any missing factors?

9. Primary Outcome • Primary outcome • Composite of death or survival with one or more of • Retinopathy of prematurity: Grade 3 through 5 (blinded) • Bronchopulmonary dysplasia: supplemental oxygen at postconceptual age of 36 weeks or later (clinical) • Brain injury: presence of cystic periventricular leukomalacia, intra-parenchymal echodensity, porencephalic cyst, or ventriculomegaly on the “worst” cranial ultrasound available before discharge (blinded) • All independently associated with neurodevelopment outcome at 18 months’ age • Assessments performed in 1st week and pre-discharge from tertiary care hospital

10. Primary Outcome • Statistics • Sample size of 424 neonates based on detecting with 90% power an absolute risk reduction of 15% in either direction (two-sided  of 0.05) for primary outcome

11. Primary Outcome • Median followup of 12 weeks • Followup complete

12. Secondary Outcomes • Hematologic and Transfusion Outcomes • Separation between groups of about 10g/L by 4 weeks • No difference for other secondary outcomes • Duration of ventilatory support, growth, length of hospital stay

13. Authors’ conclusions • The present findings provide evidence that transfusion thresholds in ELBW infants can be moved downwards by at least 10g/L without incurring a clinically important increase in the risk of death or major neonatal morbidity

14. Critical Appraisal • Strengths • Large difficult multi-centre trial • Predefined primary outcome • Powered to detect difference of 15% • Weaknesses • Clinicians and caregivers not blinded (but most outcomes assessed blindly) • Non-algorithm transfusions given (but still kept separation in Hb) • Did not dictate how often Hb measured

15. Critical Appraisal • Are the results valid? Did groups begin the study with similar prognosis? • Randomized? Yes • Randomization concealed? Yes • Intention to treat? Yes • Groups similar at baseline? Yes Did groups retain similar prognosis after starting? • Were pts blinded? Yes • Were clinicians blinded? No • Were outcomes assessors blinded? Yes (exc BPD) • Was followup complete? Yes Guyatt G, Rennie D. Users’ Guide to the Medical Literature.

16. Critical Appraisal • What are the results? • What was the treatment effect? 2.7% • How precise was the estimate? -3.7 to 9% • How can I apply the results to patient care? • Were the study pts similar to my pts? Yes • Were all clinically important outcomes considered? Yes • Are the likely treatment benefits worth the potential harm and costs? Yes? Guyatt G, Rennie D. Users’ Guide to the Medical Literature.

17. 2005: Iowa Trial • RCT in 100 preterm infants (500-1300g) • Liberal vs. restrictive transfusion group • Powered to detect difference in # of transfusions • Results • Greater separation of Hb 27 g/L • More RBC transfusions (5.2  4.5 vs 3.3  2.9) • No difference in donors (2.8  2.5 vs 2.2  2.0) • No difference in infants not transfused (12% vs 10%) Bell et al. Pediatrics 2005;115:1685-91

18. 2005: Iowa Trial • Secondary neurologic outcomes • Grade 4 hemorrhages developed by 9 days of age • PVL assessed in late ultrasound examinations Bell et al. Pediatrics 2005;115:1685-91

19. 2005: Iowa Trial • Authors’ conclusions: results suggest that growing use of restrictive RBC transfusion is not without cost and should be reexamined carefully • Criticisms • Not powered for brain US outcomes • No baseline ultrasounds • Followup incomplete for this outcome • All 100 pts had day 7 ultrasounds but only 52 (24 liberal and 28 restrictive) had day 42 examinations • Presumably same mechanism of Grade 3 vs. 4 Bell et al. Pediatrics 2005;115:1685-91

20. 2005: Iowa Trial • Secondary neurologic outcomes • Grade 4 hemorrhages developed by 9 days of age • PVL assessed in late ultrasound examinations Bell et al. Pediatrics 2005;115:1685-91

21. The PINT Editorial Bell EF. J Pediatr 2006;149:287-9

22. Conclusions • PINT study: transfusion thresholds in ELBW infants can be moved downward by at least 10 g/L without incurring a clinically important increase in the risk of death or major neonatal morbidity

23. Additional comments • Composite outcome: always beware • Was it appropriate? • Are the components equally important to patients? (is BPD as important as ROP or brain injury or death) • Are they occurring at the same frequency? Yes in this study • This is a superiority study and not a non-inferiority study so have to be careful about conclusions • If you were to do another study comparing a lower 10g threshold and found no difference, could you really say that decreasing by 20g has no effect on outcomes? • Need to proceed with caution

24. Additional comments • Another study coming PINTOS • Looking at neurodevelopmental outcomes at 18 months: composite of death, CP, cognitive delay, blindness and deafness showing no difference between the groups • Also now with combination of TRICC/PINT and montreal pediatric study that we can say transfusion does not need to be based solely on a number and perhaps a lower Hb level may be appropriate in some cases.