A prospective, randomized, double-blind controlled trial of acetaminophen and diphenhydramine for the prevention of tran

1. A prospective, randomized, double-blind controlled trial of acetaminophen and diphenhydramine for the prevention of transfusion reactions

2. Background • Study done in North Carolina with bedside leukoreduction • Rates of febrile reactions: • RBC transfusions: 0.3-6% • With prestorage leukoreduction: 0.2% • Platelet transfusions: 1-38% • With prestorage leukoreduction: 0.2%

3. Background • Canada has prestorage leukoreduction • Rates of febrile reactions: • RBC transfusions: 0.3% • Platelet transfusions: 10% • O’Brien et al. Current incidence and estimated residual risk of transfusion-transmitted infections in donations made to Canadian Blood Services. Transfusion 2007;47:316-325.

4. Pathophysiology • The recipient’s leukocyte antibodies form antibody-antigen complexes with the donor leukocytes • This interaction actives effector cells (monocytes and B cells) to produce and release IL-1, IL-6, TNF-α and other proinflammatory mediators • These same inflammatory substances can accumulate in blood products during storage and cause febrile reactions in the absence of recipient WBC antibodies

5. Background • Isolated chills and rigors without fever were not considered febrile reactions in this study

6. Background • Study • Rates of allergic transfusion reactions: • 0.4-3% • Not mitigated by leukoreduction • Canada • Rates of allergic transfusion reactions: • 1%

7. Pathophysiology • Recipient antibodies react with plasma proteins or other substances in the donor unit • Preformed recipient IgE on mast cells and basophils interacting with this antigen leads to activation and degranulation • Mast cell and basophil degraulation releases histamine, adenosine, chemotactic factors and enzymes resulting in allergic symptoms

8. Question • Most febrile reactions respond to acetaminophen (and allergic reactions to diphenhydramine) • Can we use these medications prophylactically to prevent these reactions?

9. Why is this important? • These reactions can be uncomfortable or distressing for the patient • These reactions are very common and have financial impact • Utilizes limited nursing resources • Utilizes physician resources • May increase product utilization • Early severe reactions may be confused with these common, minor reactions

10. What are the disadvantages? • 68-80% of patietns will be prophylaxed • Acetaminophen may mask fever unrelated to transfusion (infection) • Rare side effects include hepatotoxicity • Sedation with diphenhydramine may be bothersome to an otherwise active patient • Cost ($40,000) • Ethical considerations

11. Method • Randomized, double-blind placebo controlled study • 315 BMT patients aged 18-65 • Exclusions: • Allergy to the study medications • Documented history of febrile or allergic transfusion reaction

12. Method • Randomized by the pharmacist to receive either 500 mg acetaminophen and 25 mg diphenhydramine or placebo 30 minutes before RBC or platelet transfusion • Using blocked randomization • All caregivers/members of the team were blinded throughout the study duration and data collection

13. Method • The PI reviewed the medical record to determine if a transfusion occurred • Patients were removed from the study once a transfusion reaction was documented

14. Statistical analysis • The study was designed to accrue 320 patients • 90% power for detecting a HR of 0.4 (treatment relative to placebo) at the 10% one-sided level of significance • Assumes 10% of the patients would have reactions • Equal type 1 and type 2 error rates were chosen because it was equally important to protect against falsely rejecting or falsely accepting the null hypothesis

16. Results

17. Results • There was no difference between the number of reactions in the placebo versus the experimental arm (p=0.433)

18. Problems • The rate of reactions are not in keeping with expected rates • FNHTRs: 0.62% • Non-traditional definition of FNHTRs • Allergic: 0.86%

19. Problems • “A log rank test was used to assess the unadjusted difference between groups in the number of transfusions received before a reaction was noted” • “If the Kaplan-Meier survival curves cross then this is clear departure from proportional hazards, and the log rank test should not be used” • BMJ Statistics at Square One • http://www.bmj.com/collections/statsbk/12.dtl

20. Problems • Therefore, we can’t rely on the conclusion: “the number of transfusions until a febrile reaction was significantly greater (at the pre-specified 0.1 level of significance) for patients receiving the active drug (one sided p=0.074)” • Invalid conclusion: “the standard practice. . . may reduce febrile reactions”

21. Problems • No transfusions were excluded when study drugs were administered off-study • 33% of transfusions were administered under these circumstances • Re-analysis excluding these transfusions and results were similar except for the fact that the rate of reactions was higher • Insufficient power • Does this violate intention to treat?

22. What were the results? • Prophylactic administration of acetaminophen and diphenhydramine does not significantly decrease the rate of transfusion reactions in BMT patients receiving RBCs or platelets who have not previously had an allergic reaction or FNHTR

23. How large was the treatment effect? • There was no difference between the frequency of allergic reactions or FNHTRs in the experimental arm versus the placebo arm • The authors claim the number of febrile transfusion reactions received before the first febrile reaction was significantly greater for patients receiving the active drug than for placebo

24. Are the results valid? • Have the results been systematically biased? • Excluded patients with previous reactions • Patients removed from study after first reaction • Average of 13 transfusions/patient • Removal of “reactors”

25. Was the assignment of patients to treatment randomized? • Patients were randomized by the pharmacist using blocked randomization

26. What is randomization? • The process of assigning participants to treatment groups in a known but unpredictable fashion • The participant should have an equal chance of being assigned to any of the treatment groups • It helps ensure that the treatment and control groups will have similar characteristics of both known and unknown factors • Any difference between groups will occur only by chance (avoids systematic bias)

27. Different types of randomization • Fixed randomization • Probability of allocation to each treatment group remains constant • Adaptive randomization • Probability of being assigned to a treatment group changes as a function of such variables as the number of patients assigned to the group, the subjects’ baseline characteristics, or observed outcomes

28. Fixed allocation randomization • Assigns the intervention to participants with a pre-specified probability, usually equal, and that allocation probability is not altered as the study progresses • Simple randomization • Blocked randomization • Stratified randomization

29. Simple randomization • Simple randomization • Coin toss or random number generator • Advantages include simplicity and in the long run probability dictates that the groups will be equivalent • Disadvantages are that for small to medium sample sizes, can end up with very unequal results • If randomizing 100 patients, there in only an 8% chance that there will be 50 patients in either group

30. Blocked Randomization • In a trial of 60 subjects there could be 10 consecutive blocks of 6, each containing 3 allocations to the control group and 3 allocations to the treatment group • Advantages: ensures the same number of patients in both the control and experimental groups • Even if the study is stopped early, the maximum imbalance in sample size is half the size of the block • Disadvantages: more complicated analysis

31. Blocked Randomization • There are six different ways to allocate four patients to two groups • AABB • ABAB • ABBA • BABA • BAAB • BBAA

32. Blocked randomization • Roll a dice to choose the allocation pattern for the upcoming block • Each of the six patterns has the same likelihood of being chosen • This pattern guarantees that the groups will be balanced after every 4 patients • The maximum imbalance between the groups is 2 patients

33. Stratified randomization • Stratified random allocation involves first identifying important prognostic factors and then separately randomising blocks containing different levels of the prognostic factor • The prognostic factors that are most commonly stratified are disease severity and, in multi-site, trials, the site at which the subject is treated

34. Stratified randomization • Advantages • Potentially increases statistical power • Disadvantages • it is not practically possible to stratify by all important prognostic factors • stratification must be blocked if it is to be useful, but it is difficult to match block sizes so that each stratum fills at approximately the same time • as the trial nears completion, the researchers may have to discontinue recruitment into one stratum while they wait for another stratum to fill up

35. Were all patients who entered the trial properly accounted for at its conclusion? • All transfusion events were accounted for • Even those events which occurred while study medications were being used off-study • No “loss to follow up” • Events were analyzed in the groups to which they were randomized

36. Were patients, their clinicians and study personnel “blind” to treatment? • All study personnel (other than the pharmacist) were blinded to the allocation of patients

37. Were the groups similar at the start of the trial?

38. Aside from the experimental intervention, were the groups treated equally? • Presumably there should have been no difference in the way that the two groups were managed

39. Will the results help me in caring for my patients?

40. Can the results be applied to my patient care? • The patient population (BMT patients) accounts for a substantial portion of patients receiving blood products in our hospital • The authors excluded patients who had had previous reactions, which is a population of particular interest

41. Were all clinically important outcomes considered? • Used criteria (somewhat restrictive for febrile) to determine whether patients did or did not have reactions • It might be interesting to also have had subjective patient comfort as an outcome

42. Are the likely treatment benefits worth the potential harm and cost? • In this case, the authors were unable to show any difference in the rates of transfusion reactions (allergic and FNHTRs) between the patients who received premedication and those who did not • Therefore, the treatment has no benefit • Potential harm is likely to be minimal • The impact on cost is probably moderate

43. Conclusion • In conclusion, there is no evidence the prophylaxis with acetaminophen and diphenhydramine prevents allergic or FNHTRs in BMT patients who have not experienced a previous reaction • Recommendation: Do not prophylax BMT patients with no history of reaction, but treat reactions as they occur