A prospective, randomized, double-blind controlled trial of acetaminophen and diphenhydramine for...
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Transcript of A prospective, randomized, double-blind controlled trial of acetaminophen and diphenhydramine for...
A prospective, randomized, double-blind controlled trial of acetaminophen and diphenhydramine for the prevention of transfusion reactions
BackgroundStudy done in North Carolina with
bedside leukoreductionRates of febrile reactions:
RBC transfusions: 0.3-6% With prestorage leukoreduction: 0.2%
Platelet transfusions: 1-38% With prestorage leukoreduction: 0.2%
BackgroundCanada has prestorage leukoreductionRates 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.
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
Background Isolated chills and rigors without fever
were not considered febrile reactions in this study
BackgroundStudy
Rates of allergic transfusion reactions: 0.4-3% Not mitigated by leukoreduction
Canada Rates of allergic transfusion reactions:
1%
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
QuestionMost febrile reactions respond to
acetaminophen (and allergic reactions to diphenhydramine)
Can we use these medications prophylactically to prevent these reactions?
Why is this important?These reactions can be uncomfortable
or distressing for the patientThese 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
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
MethodRandomized, double-blind placebo
controlled study315 BMT patients aged 18-65Exclusions:
Allergy to the study medications Documented history of febrile or allergic
transfusion reaction
MethodRandomized 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
MethodThe PI reviewed the medical record to
determine if a transfusion occurredPatients were removed from the study
once a transfusion reaction was documented
Statistical analysisThe 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
ResultsThere was no difference between the
number of reactions in the placebo versus the experimental arm (p=0.433)
ProblemsThe rate of reactions are not in keeping
with expected rates FNHTRs: 0.62%
Non-traditional definition of FNHTRs Allergic: 0.86%
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
ProblemsTherefore, 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”
ProblemsNo 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?
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
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
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”
Was the assignment of patients to treatment randomized?
Patients were randomized by the pharmacist using blocked randomization
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)
Different types of randomizationFixed 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
Fixed allocation randomizationAssigns the intervention to participants
with a pre-specified probability, usually equal, and that allocation probability is not altered as the study progresses
Simple randomizationBlocked randomizationStratified randomization
Simple randomizationSimple 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
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
Blocked RandomizationThere are six different ways to allocate
four patients to two groups AABB ABAB ABBA BABA BAAB BBAA
Blocked randomizationRoll a dice to choose the allocation
pattern for the upcoming blockEach of the six patterns has the same
likelihood of being chosenThis pattern guarantees that the groups
will be balanced after every 4 patients The maximum imbalance between the
groups is 2 patients
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
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
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
Were patients, their clinicians and study personnel “blind” to treatment?All study personnel (other than the
pharmacist) were blinded to the allocation of patients
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
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
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
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