Transcript A prospective, randomized, double

A prospective, randomized,
double-blind controlled trial
of acetaminophen and
diphenhydramine for the
prevention of transfusion
reactions
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%
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.
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
Background
 Study
 Rates
of allergic transfusion reactions:
0.4-3%
 Not mitigated by leukoreduction

 Canada
 Rates

1%
of allergic transfusion reactions:
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
Question
 Most
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 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
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
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
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
 All
blocked randomization
caregivers/members of the team
were blinded throughout the study
duration and data collection
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
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

Results
Results
 There
was no difference between the
number of reactions in the placebo
versus the experimental arm (p=0.433)
Problems
 The
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

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”
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?

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 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
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

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
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 Randomization
 There
are six different ways to allocate
four patients to two groups
 AABB
 ABAB
 ABBA
 BABA
 BAAB
 BBAA
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
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 offstudy
 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
Were the groups similar at the
start of the trial?
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
Will the results help me in
caring for my patients?
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
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