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Effective treatment of heavy and/or

prolonged menstrual bleeding without


organic cause: pooled analysis of two
multinational, randomised, double-
blind, placebo-controlled trials of
oestradiol valerate and dienogest
THERAPY STUDY:
1. Are the results of the trial valid?
(Internal Validity)
2. What question did the study ask?
PICO
• Patients wanita hamil dengan risiko tinggi
preeklamsi
• Intervention gabungan dari L-Arginine
dengan vitamin antioksidan
• Comparison vitamin antioksidan dg placebo
• Outcome(s) L-Arginine dan vitamin anti
oksidan menurunkan angka kejadian
preeklamsi
1a. R- Was the assignment of patients to treatments randomised?
What is best? Where do I find the information?
Centralised computer randomisation is ideal and often The Methods should tell you how patients were allocated
used in multi-centred trials. Smaller trials may use an to groups and whether or not randomisation was
independent person (e.g, the hospital pharmacy) to concealed.
“police” the randomization.
This paper: Yes  No  Unclear 
Comment: pada penelitian ini penulis menjelaskan pengambilan sampel wanita hamil dengan
risiko tinggi preeklamsi diambil secara acak dengan cara staff dari departemen Obstetri
mereview pasien yang memiliki kualitas untuk penelitian. Pasien akan menerima satu dari
treatment tersebut secara acak. Investigator mengacak menggunakan centralised computer
randomisation.

1b. R- Were the groups similar at the start of the trial?


What is best? Where do I find the information?
If the randomisation process worked (that is, achieved The Results should have a table of "Baseline
comparable groups) the groups should be similar. The Characteristics" comparing the randomized groups on a
more similar the groups the better it is. number of variables that could affect the outcome (ie. age,
treatment tersebut secara acak. Investigator mengacak menggunakan centralised computer
randomisation.

1b. R- Were the groups similar at the start of the trial?


What is best? Where do I find the information?
If the randomisation process worked (that is, achieved The Results should have a table of "Baseline
comparable groups) the groups should be similar. The Characteristics" comparing the randomized groups on a
more similar the groups the better it is. number of variables that could affect the outcome (ie. age,
There should be some indication of whether differences risk factors etc). If not, there may be a description of group
between groups are statistically significant (ie. p values). similarity in the first paragraphs of the Results section.
This paper: Yes  No  Unclear 
Comment:pada hasil peenlitian, peneliti telah menampilkan table Karakteritik dasar pasien
dari tiga kelompok yang masing-masing memiliki P = > 0,05 artinya ke-3 kelompok itu memiliki
karakteristik yang sama

2a. A – Aside from the allocated treatment, were groups treated equally?
What is best? Where do I find the information?
Apart from the intervention the patients in the different Look in the Methods section for the follow-up schedule,
groups should be treated the same, eg., additional and permitted additional treatments, etc and in Results for
2a. A – Aside from the allocated treatment, were groups treated equally?
What is best? Where do I find the information?
Apart from the intervention the patients in the different Look in the Methods section for the follow-up schedule,
groups should be treated the same, eg., additional and permitted additional treatments, etc and in Results for
treatments or tests. actual use.
This paper: Yes  No  Unclear 
Comment: pada penelitian ini participant dijadwalkan untuk melakukan klinikal follow up setiap
3-4 minggu, antara lain mengukur tekanan arteri, pengambilan sampel darah 10 ml, menampung
urin 24 jam sehari sebelum follow up, pasien diminta mencatat konsumsi bars, dan peneliti
juga memberikan edukasi tentang nutrisi selama kehamilan pada semua partisipant

2b. A – Were all patients who entered the trial accounted for? – and were
they analysed in the groups to which they were randomised?
What is best? Where do I find the information?
Losses to follow-up should be minimal – preferably less The Results section should say how many patients were
than 20%. However, if few patients have the outcome of andomised (eg., Baseline Characteristics table) and how
interest, then even small losses to follow-up can bias the many patients were actually included in the analysis. You
results. Patients should also be analysed in the groups to will need to read the results section to clarify the number
which they were randomised – ‘intention-to-treat analysis’. and reason for losses to follow-up.
This paper: Yes  No  Unclear 
Comment: pada penelitian ini peneliti mengambil partisipan sebanyak 696 wanita. Partisipan
yang memenuhi criteria inklusi sebanyak 672 dan yang memenuhi criteria eksklusi sebanyak
24 partisipant. Dari clinical follow up, kurang dari 5% yang tidak terlewat untung dikunjungi
dari 3 grup tersebut.
3. M - Were measures objective or were the patients and clinicians kept
“blind” to which treatment was being received?
What is best? Where do I find the information?
It is ideal if the study is ‘double-blinded’ – that is, both First, look in the Methods section to see if there is some
patients and investigators are unaware of treatment mention of masking of treatments, eg., placebos with the
allocation. If the outcome is objective (eg., death) then same appearance or sham therapy. Second, the Methods
blinding is less critical. If the outcome is subjective (eg., section should describe how the outcome was assessed
symptoms or function) then blinding of the outcome and whether the assessor/s were aware of the patients'
assessor is critical. treatment.
This paper: Yes  No  Unclear 
Comment: pada penelitian ini peneliti menjelaskan bahwa Pasien tidak mengetahui dan tidak
bisa membedakan isi dari amplop tersebut karena penampilannya sama dan tidak ada
perbedaan rasa. Hanya investigator utama yang mengetahui kode dari masing-masing amplop
tertutup yang berisi treatment tersebut.
What were the results?
1. How large was the treatment effect?
Most often results are presented as dichotomous outcomes (yes or not outcomes that happen or don't happen) and can
include such outcomes as cancer recurrence, myocardial infarction and death. Consider a study in which 15% (0.15) of
the control group died and 10% (0.10) of the treatment group died after 2 years of treatment. The results can be
expressed in many ways as shown below.

What is the measure? What does it mean?


Relative Risk (RR) = risk of the outcome in the The relative risk tells us how many times more likely it is that
treatment group / risk of the outcome in the control an event will occur in the treatment group relative to the control
group. group. An RR of 1 means that there is no difference between the
two groups thus, the treatment had no effect. An RR < 1 means
that the treatment decreases the risk of the outcome. An RR > 1
means that the treatment increased the risk of the outcome.
In our example, the RR = 0.10/0.15 = 0.67 Since the RR < 1, the treatment decreases the risk of death.

Absolute Risk Reduction (ARR) = risk of the The absolute risk reduction tells us the absolute difference in the
outcome in the control group - risk of the outcome rates of events between the two groups and gives an indication
in the treatment group. This is also known as the of the baseline risk and treatment effect. An ARR of 0 means
absolute risk difference. that there is no difference between the two groups thus, the
treatment had no effect.
In our example, the ARR = 0.15 - 0.10 = 0.05 or 5% The absolute benefit of treatment is a 5% reduction in the death
In our example, the RR = 0.10/0.15 = 0.67 Since the RR < 1, the treatment decreases the risk of death.

Absolute Risk Reduction (ARR) = risk of the The absolute risk reduction tells us the absolute difference in the
outcome in the control group - risk of the outcome rates of events between the two groups and gives an indication
in the treatment group. This is also known as the of the baseline risk and treatment effect. An ARR of 0 means
absolute risk difference. that there is no difference between the two groups thus, the
treatment had no effect.
In our example, the ARR = 0.15 - 0.10 = 0.05 or 5% The absolute benefit of treatment is a 5% reduction in the death
rate.
Relative Risk Reduction (RRR) = absolute risk The relative risk reduction is the complement of the RR and is
reduction / risk of the outcome in the control group. probably the most commonly reported measure of treatment
An alternative way to calculate the RRR is to effects. It tells us the reduction in the rate of the outcome in the
subtract the RR from 1 (eg. RRR = 1 - RR) treatment group relative to that in the control group.
In our example, the RRR = 0.05/0.15 = 0.33 or 33% The treatment reduced the risk of death by 33% relative to that
Or RRR = 1 - 0.67 = 0.33 or 33% occurring in the control group.
Number Needed to Treat (NNT) = inverse of the The number needed to treat represents the number of patients
ARR and is calculated as 1 / ARR. we need to treat with the experimental therapy in order to
prevent 1 bad outcome and incorporates the duration of
treatment. Clinical significance can be determined to some
extent by looking at the NNTs, but also by weighing the NNTs
against any harms or adverse effects (NNHs) of therapy.
In our example, the NNT = 1/ 0.05 = 20 We would need to treat 20 people for 2 years in order to prevent
1 death.
2. How precise was the estimate of the treatment effect?
The true risk of the outcome in the population is not known and the best we can do is estimate the true risk based on
the sample of patients in the trial. This estimate is called the point estimate. We can gauge how close this estimate is
1. Pada hasil penelitian ini didapatkan bahwa L-arginine+vitamin lebih menurunkan
resiko pre-eklamsia/eclamsia dibanding dengan placebo dilihat dari ARR 0,17
(ARR≠0) dan RR 0,42 (RR<1). L-arginine+vitamin dapat menurunkan resiko pre-
eklamsia/eclamsia sebanyak 17% .

Vitamins lebih menurunkan resiko pre-eklamsia/eclamsia dibanding dengan


placebo dilihat dari ARR 0,07 (ARR≠0) dan RR 0,72 (RR<1). Vitamin dapat
menurunkan resiko pre-eklamsia/eclamsia sebanyak 7%.

Sedangkan L-arginine+vitamin lebih menurunkan resiko pre-eklamsia/eclamsia


dibanding dengan vitamin dilihat dari ARR 0,09 (ARR≠0) dan RR 0,56 (RR<1). L-
arginine+vitamin dapat menurunkan resiko pre-eklamsia/eclamsia sebanyak 9% .
In our example, the NNT = 1/ 0.05 = 20 We would need to treat 20 people for 2 years in order to prevent
1 death.
2. How precise was the estimate of the treatment effect?
The true risk of the outcome in the population is not known and the best we can do is estimate the true risk based on
the sample of patients in the trial. This estimate is called the point estimate. We can gauge how close this estimate is
to the true value by looking at the confidence intervals (CI) for each estimate. If the confidence interval is fairly narrow
then we can be confident that our point estimate is a precise reflection of the population value. The confidence interval
also provides us with information about the statistical significance of the result. If the value corresponding to no effect
falls outside the 95% confidence interval then the result is statistically significant at the 0.05 level. If the confidence
interval includes the value corresponding to no effect then the results are not statistically significant.
2. Pada penelitian ini didapatkan perbandingan L-arginine+vitamin dengan placebo
memiliki hasil yang signifikan dengan p value 0,001 (P<0,05) dan 95% confidence
intervals (CI) 0,28 sampai 0,62. Sehingga pemberian L-arginine+vitamin berefek
terhadap penurunan kejadian pre-eclamsia/eclamsia dibanding dengan placebo.

Perbandingan vitamin dengan placebo memiliki hasil yang tidak signifikan dengan p
value 0,52 (P>0,05) dan 95% confidence intervals (CI) 0,54 sampai 1,02.
Sehingga pemberian vitamin tidak berefek terhadap penurunan kejadian pre-
eclamsia/eclamsia dibanding dengan placebo.

Perbandingan L-arginine+vitamin dengan vitamin memiliki hasil yang signifikan


dengan p value 0,004 (P<0,05) dan 95% confidence intervals (CI) 0,37 sampai
0,85. Sehingga pemberian L-arginine+vitamin berefek terhadap penurunan
kejadian pre-eclamsia/eclamsia dibanding dengan vitamin.
Will the results help me in caring for my patient? (ExternalValidity/Applicability)
The questions that you should ask before you decide to apply the results of the study to your patient are:
 Is my patient so different to those in the study that the results cannot apply?
 Is the treatment feasible in my setting?
 Will the potential benefits of treatment outweigh the potential harms of treatment for my patient?