CRITICAL APPRAISAL

TOPIC (THERAPEUTICS)
STACEY DENISE ALZATE
 CLINICAL SCENARIO
A 40 year old male sought consult at the ER due to 1 day history of
increased sleeping time, however arousable to pain, coherent, and with
spontaneous movement of extremities. 2 hours PTA, patient was noted to
have incomprehensible speech, with decreasing mental status, hence
admission.
He was previously diagnosed with Chronic Hepatitis B infection last
April 2017.
After reviewing the patient’s chart, a curious medical intern asked
the resident in charge if adding rifaximin to lactulose would have a
beneficial effect in the treatment of hepatic encephalopathy in terms of
preventing the risk of dying.
CLINICAL QUESTION
Among patients with acute hepatic
encephalopathy, how effective is the addition of
Rifaximin to Lactulose in the treatment of
hepatic encephalopathy in terms of preventing
the risk of dying?
Research Article
 Assessing Directness: PEO
CLINICAL QUESTION RESEARCH QUESTION
POPULATION 40 year old male with Patients aged 37-40
acute hepatic with overt hepatic
encephalopathy encephalopathy
EXPOSURE / Rifaximin + Lactulose Rifaximin+ Lactulose
INTERVENTION
OUTCOME Treatment of Hepatic Treatment of Hepatic
Encephalopathy in Encephalopathy in
terms of preventing terms of HE reversal
the risk of dying and death
Appraising
Validity
 Appraising Validity
Questions YES OR NO PAGE NUMBER and Paragraph Number
1. Were patients randomly assigned YES Page 2 under Methods Study Design;
to treatment groups
Paragraph 1
2. Was allocation concealed? YES Page 2 under Methods Study Design;
Paragraph 1
3. Were baseline characteristics YES Page 3 Table 1
similar at the start of the trial?
4. Were Patients blinded to YES Page 2 under Methods Study Design;
treatment assignments?
Paragraph 1
5. Were caregivers blinded to YES Page 2 under Methods Study Design;
treatment assignments?
Paragraph 1
6. Were outcome assessors blinded YES Page 2 under Methods Study Design;
to treatment assignments?
Paragraph 1
7 Were all patients analyzed in the YES Page 3 Figure 1
groups to which they were originally
randomized?
8. Was follow-up rate adequate NO Page 3 Figure 1
Validity
1. Were patients randomly assigned to treatment groups
 Appraising Validity
Questions YES OR NO PAGE NUMBER and Paragraph Number
1. Were patients randomly assigned YES Page 2 under Methods Study Design;
to treatment groups
Paragraph 1
2. Was allocation concealed? YES Page 2 under Methods Study Design;
Paragraph 1
3. Were baseline characteristics YES Page 3 Table 1
similar at the start of the trial?
4. Were Patients blinded to YES Page 2 under Methods Study Design;
treatment assignments?
Paragraph 1
5. Were caregivers blinded to YES Page 2 under Methods Study Design;
treatment assignments?
Paragraph 1
6. Were outcome assessors blinded YES Page 2 under Methods Study Design;
to treatment assignments?
Paragraph 1
7 Were all patients analyzed in the YES Page 3 Figure 1
groups to which they were originally
randomized?
8. Was follow-up rate adequate NO Page 3 Figure 1
Validity
2. Was allocation concealed?
 Appraising Validity
Questions YES OR NO PAGE NUMBER and Paragraph Number
1. Were patients randomly assigned YES Page 2 under Methods Study Design;
to treatment groups
Paragraph 1
2. Was allocation concealed? YES Page 2 under Methods Study Design;
Paragraph 1
3. Were baseline characteristics YES Page 3 Table 1
similar at the start of the trial?
4. Were Patients blinded to YES Page 2 under Methods Study Design;
treatment assignments?
Paragraph 1
5. Were caregivers blinded to YES Page 2 under Methods Study Design;
treatment assignments?
Paragraph 1
6. Were outcome assessors blinded YES Page 2 under Methods Study Design;
to treatment assignments?
Paragraph 1
7 Were all patients analyzed in the YES Page 3 Figure 1
groups to which they were originally
randomized?
8. Was follow-up rate adequate NO Page 3 Figure 1
 Validity
3. Were baseline characteristics similar at the start of the
trial?
 Appraising Validity
Questions YES OR NO PAGE NUMBER and Paragraph Number
1. Were patients randomly assigned YES Page 2 under Methods Study Design;
to treatment groups
Paragraph 1
2. Was allocation concealed? YES Page 2 under Methods Study Design;
Paragraph 1
3. Were baseline characteristics YES Page 3 Table 1
similar at the start of the trial?
4. Were Patients blinded to YES Page 2 under Methods Study Design;
treatment assignments?
Paragraph 1
5. Were caregivers blinded to YES Page 2 under Methods Study Design;
treatment assignments?
Paragraph 1
6. Were outcome assessors blinded YES Page 2 under Methods Study Design;
to treatment assignments?
Paragraph 1
7 Were all patients analyzed in the YES Page 3 Figure 1
groups to which they were originally
randomized?
8. Was follow-up rate adequate NO Page 3 Figure 1
Validity
4. Were Patients blinded to treatment assignments?
 Appraising Validity
Questions YES OR NO PAGE NUMBER and Paragraph Number
1. Were patients randomly assigned YES Page 2 under Methods Study Design;
to treatment groups
Paragraph 1
2. Was allocation concealed? YES Page 2 under Methods Study Design;
Paragraph 1
3. Were baseline characteristics YES Page 3 Table 1
similar at the start of the trial?
4. Were Patients blinded to YES Page 2 under Methods Study Design;
treatment assignments?
Paragraph 1
5. Were caregivers blinded to YES Page 2 under Methods Study Design;
treatment assignments?
Paragraph 1
6. Were outcome assessors blinded YES Page 2 under Methods Study Design;
to treatment assignments?
Paragraph 1
7 Were all patients analyzed in the YES Page 3 Figure 1
groups to which they were originally
randomized?
8. Was follow-up rate adequate NO Page 3 Figure 1
Validity
5. Were caregivers blinded to treatment assignments?
 Appraising Validity
Questions YES OR NO PAGE NUMBER and Paragraph Number
1. Were patients randomly assigned YES Page 2 under Methods Study Design;
to treatment groups
Paragraph 1
2. Was allocation concealed? YES Page 2 under Methods Study Design;
Paragraph 1
3. Were baseline characteristics YES Page 3 Table 1
similar at the start of the trial?
4. Were Patients blinded to YES Page 2 under Methods Study Design;
treatment assignments?
Paragraph 1
5. Were caregivers blinded to YES Page 2 under Methods Study Design;
treatment assignments?
Paragraph 1
6. Were outcome assessors blinded YES Page 2 under Methods Study Design;
to treatment assignments?
Paragraph 1
7. Were all patients analyzed in the YES Page 3 Figure 1
groups to which they were originally
randomized?
8. Was follow-up rate adequate NO Page 3 Figure 1
6. Were outcome assessors blinded to treatment
assignments?
 Appraising Validity
Questions YES OR NO PAGE NUMBER and Paragraph Number
1. Were patients randomly assigned YES Page 2 under Methods Study Design;
to treatment groups
Paragraph 1
2. Was allocation concealed? YES Page 2 under Methods Study Design;
Paragraph 1
3. Were baseline characteristics YES Page 3 Table 1
similar at the start of the trial?
4. Were Patients blinded to YES Page 2 under Methods Study Design;
treatment assignments?
Paragraph 1
5. Were caregivers blinded to YES Page 2 under Methods Study Design;
treatment assignments?
Paragraph 1
6. Were outcome assessors blinded YES Page 2 under Methods Study Design;
to treatment assignments?
Paragraph 1
7. Were all patients analyzed in the YES Page 3 Figure 1
groups to which they were originally
randomized?
8. Was follow-up rate adequate NO Page 3 Figure 1
Validity

7. Were all patients analyzed in the

groups to which they were
originally randomized?
 Appraising Validity
Questions YES OR NO PAGE NUMBER and Paragraph Number
1. Were patients randomly assigned YES Page 2 under Methods Study Design;
to treatment groups
Paragraph 1
2. Was allocation concealed? YES Page 2 under Methods Study Design;
Paragraph 1
3. Were baseline characteristics YES Page 3 Table 1
similar at the start of the trial?
4. Were Patients blinded to YES Page 2 under Methods Study Design;
treatment assignments?
Paragraph 1
5. Were caregivers blinded to YES Page 2 under Methods Study Design;
treatment assignments?
Paragraph 1
6. Were outcome assessors blinded YES Page 2 under Methods Study Design;
to treatment assignments?
Paragraph 1
7 Were all patients analyzed in the YES Page 3 Figure 1
groups to which they were originally
randomized?
8. Was follow-up rate adequate NO Page 3 Figure 1
 Validity
8. Was follow-
up rate
adequate?
Results
APPRAISING RESULTS:
QUESTION #1: HOW LARGE WAS THE EFFECT
OF TREATMENT?
Results
In all, 48 (76 %) patients in group A compared with 25 (44 %) patients
in group B had complete reversal of HE ( P = 0 .004) within 10 days.
Patients in lactulose plus rifaximin group had shorter hospital stay as
compared with lactulose-alone group (5.8 ± 3.4 vs. 8.2 ± 4.6 days,
P = 0.001).
There was a significant decrease in mortality in the lactulose plus
rifaximin group (15 (24 % ) vs. lactulose alone (28 (49.1 % ), P <0.05
MEASURES OF EFFECTIVENESS FOR
DICHOTOMOUS OUTCOMES
RESULTS
◦ RELATIVE RISK
◦ Risk of the outcome in the treatment group /
Risk of the outcome in the control group
 RESULTS
RELATIVE RISK
Risk of the outcome in the treatment group / Risk of
the outcome in the control group
◦ 0.23/0.49
◦ =0.46

◦ (The risk of dying among patients with hepatic

encephalopathy given with Lactulose + Rifaximin is
46% of what it was)
 RESULTS
RELATIVE RISK REDUCTION
◦ 1-RR
◦ 1-0.46
◦ = 0.54 0r 54%

◦ Patients with hepatic encephalopathy given with

Lactulose + Rifaximin lost 54% of their risk of dying
compared to patients given with lactulose alone
RESULTS
ABSOLUTE RISK REDUCTION
◦ Risk of the outcome in the control group –
Risk of the outcome in the treatment group
 RESULTS
ABSOLUTE RISK REDUCTION
◦ Risk of the outcome in the control group – Risk of the
outcome in the treatment group
◦ 0.49-0.24
◦ 49%-24%
◦ =0.25 or 25%
◦ (Patients with hepatic encephalopathy have 25%
reduction in their risk of dying when given with
Lactulose + Rifaximin compared to patients given
Lactulose alone)
RESULTS
NUMBER NEEDED TO TREAT
◦ Inverse of the ARR
◦ 1/ARR
 RESULTS
NUMBER NEEDED TO TREAT
◦ Inverse of the ARR
◦ 1/ARR or 100/ARR in %
◦ 1/0.25 or 100/25
◦4

◦ (If 100 patients were treated, 25 would be prevented

from developing bad outcome which is risk of dying,
therefore if 25 out of 100 patients benefit from
Rifaximin +Lactuose, the NNT for one patient to benefit
is about 4%)
 What are the results?
Outcome Rc Rt RR RRR ARR NNT
Treatment of 0.49 0.23 0.46 0.54 0.25 4
hepatic 54%
encephalopat
hy in terms of <1: treatment >0: >0:
reduction in beneficial treatment treatment
the risk of beneficial beneficial
dying
Applicability
Issues
Applicability Issues
Biologic:
◦ Age: Mean of 40
◦ Gender: Majority are Men

Rifaximin acts by binding to the beta-subunit of bacterial DNAdependent RNA

polymerase resulting in inhibition of bacterial RNA synthesis

The safety and effectiveness of Rifaximin Tablets is established in patients aged 13-64

Gender: The effect of gender on the pharmacokinetics of rifaximin has not been
studied.
Applicability Issues
Socio-Economic:
◦ Price: 79 pesos per tablet to be given 3x a day for
10 days
◦ =2370
◦ NNTx2370
=4x 2370: 9,480
Availability: available in our Pharmacy
Individualizing the Result
As our patient is known to have Hepatitis B and is
currently presenting with Hepatic Encephalopathy, we
can tell the curious medical intern that lactulose +
rifaximin is effective in the treatment of hepatic
encephalopathy in terms of preventing risk of dying
Author’s Conclusion
Combination of lactulose plus rifaximin is more
effective than lactulose alone in the treatment of
overt HE.
Reviewer’s Conclusion
I agree.
Thank You!! 