A prospective, randomized, double-blind controlled trial of acetaminophen and diphenhydramine for the prevention of transfusion reactions - PowerPoint PPT Presentation

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

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


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
  • OBrien et al. Current incidence and estimated
    residual risk of transfusion-transmitted
    infections in donations made to Canadian Blood
    Services. Transfusion 200747316-325.

4
Pathophysiology
  • The recipients 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-a 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

15
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16
Results
17
Results
  • There was no difference between the number of
    reactions in the placebo versus the experimental
    arm (p0.433)

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 cant 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 p0.074)
  • 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
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