LAPORAN RESMI PRAKTIKUM FARMASI KLINIK

CRITICAL APPRAISAL FOR THERAPY

(RANDOMIZED CONTROLLED TRIAL)

DISUSUN OLEH:
KELAS C/GOLONGAN 2/KELOMPOK 3

ANGGOTA KELOMPOK:

1. GP. Wahyunanda Crista Yuda

NIM. 18/429552/FA/11817

2. Hafidh Dimas Syahputra

NIM. 18/429553/FA/11818

3. Harlina Amalia Putri

NIM. 18/429554/FA/11819

4. Hasna Nurul Izzati

NIM. 18/429555/FA/11820

PROGRAM SARJANA PROGRAM STUDI FARMASI

FAKULTAS FARMASI
UNIVERSITAS GADJAH MADA
2020
Critical Appraisal for Therapy Articles

THERAPY STUDY: Are the results of the trial valid? (Internal Validity)
What question did the study ask?
Patients – Pasien dengan COVID-19
Intervention – Penambahan hidroksiklorokuin
Comparison – Standard care
Outcome(s) – Lama recovery, kebutuhan ventilasi mekanik, kematian

Paper yang akan ditelaah

1a. R- Was the assignment of patients to treatments randomised?

What is best? Where do I find the information?

Centralised computer randomisation is ideal The Methods should tell you how patients were
and often used in multi-centred trials. Smaller allocated to groups and whether or not
trials may use an independent person (e.g., the randomisation was concealed.
hospital pharmacy) to “police” the
randomization.

This paper: Yes ☐ No ☐ Unclear ☐

Comment:

Ya, karena:
Pasien diacak menjadi dua kelompok menggunakan generator nomor acak terkomputerisasi
menggunakan pengacakan sederhana dengan rasio alokasi yang sama. Selama pengacakan,
alokasi proporsional dari setiap tingkatan klinis disamakan pada kedua kelompok.

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, The Results should have a table of "Baseline
achieved comparable groups) the groups Characteristics" comparing the randomized

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Critical Appraisal for Therapy Articles

should be similar. The more similar the groups groups on a number of variables that could
the better it is. affect the outcome (i.e., age, risk factors etc). If
not, there may be a description of group
There should be some indication of whether
similarity in the first paragraphs of the Results
differences between groups are statistically
section.
significant (i.e., p values).

This paper: Yes ☐ No ☐ Unclear ☐

Comment:

Ya, karena:
Tidak ada perbedaan substansial dalam karakteristik dasar dari kedua kelompok. Total karateristik
yang dilihat adalah 9.

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 Look in the Methods section for the follow-up
different groups should be treated the same, schedule, and permitted additional treatments,
e.g., additional treatments or tests. etc and in Results for actual use.

This paper: Yes ☐ No ☐ Unclear ☐

Comment:

Ya, karena:
Kelompok perlakuan :
1. Kelompok Hidroksiklorokuin: Kelompok ini terdiri dari 97 pasien yang menerima HCQ 400
mg dua kali sehari (pada hari 1) diikuti dengan tablet 200 mg dua kali sehari ditambahkan
ke standar perawatan yang diadopsi oleh Egyptian MOH selama 15 hari.
2. Kelompok kontrol: Kelompok ini terdiri dari 97 pasien yang hanya menerima perawatan
standar yang diadopsi oleh National MOH selama 15 hari.

Semua pasien di follow up selama 4 minggu.

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Critical Appraisal for Therapy Articles

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 – The Results section should say how many
preferably less than 20%. However, if few patients were randomised (e.g., Baseline
patients have the outcome of interest, then Characteristics table) and how many patients
even small losses to follow-up can bias the were actually included in the analysis. You will
results. Patients should also be analysed in the need to read the results section to clarify the
groups to which they were randomised – number and reason for losses to follow-up.
‘intention-to-treat analysis’.

This paper: Yes ☐ No ☐ Unclear ☐

Comment:

Ya, karena semua pasien yang mengikuti uji dihitung dan dianalisis dalam kelompok di mana
mereka dirandomisasi sehingga tidak ada kejadian loss to follow-up.

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 First, look in the Methods section to see if there
is, both patients and investigators are unaware is some mention of masking of treatments, e.g.,
of treatment allocation. If the outcome is placebos with the same appearance or sham
objective (e.g., death) then blinding is less therapy. Second, the Methods section should
critical. If the outcome is subjective (e.g., describe how the outcome was assessed and

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Critical Appraisal for Therapy Articles

symptoms or function) then blinding of the whether the assessor/s were aware of the
outcome assessor is critical. patients' treatment.

This paper: Yes ☐ No ☐ Unclear ☐

Comment:

Uji klinik ini tidak double blinded, tetapi pengukuran outcomenya objektif. Informed written
consent didapatkan dari tiap partisipan dan penelitian disetujui oleh Ethics Committee of the
Faculty of Medicine, Tanta University. Risiko dan manfaat dijelaskan kepada pasien. Outcome yang
dilihat yaitu lama recovery, kebutuhan ventilasi mekanik, dan kematian.

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Critical Appraisal for Therapy Articles

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
do not 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 The relative risk tells us how many times more likely it is
outcome in the treatment group / that an event will occur in the treatment group relative to
risk of the outcome in the control the control group. An RR of 1 means that there is no
group. 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 Since the RR < 1, the treatment decreases the risk of death.
= 0.67

This paper:
1. Pada penelitian yang dilakukan, terdapat 4 pasien (4,1%) grup HCQ dan 5 pasien (5,2%) grup
kontrol yang memerlukan mechanical ventilation, dan 6 pasien (6,2%) grup HCQ dan 5 pasien
(5,2%) grup kontrol meninggal dunia.

0,041
RR Mechanical Ventilator = = 0,79
0,052
0,062
RR Kematian = = 1,19
0,052

Penggunaan HCQ menurunkan kebutuhan penggunaan mechanical ventilator (RR <1) namun juga
menyebabkan peningkatan resiko kematian pada pasien Covid-19 RR (>1).

2. Setelah 28 hari waktu recovery, tidak ada perbedaan signifikan antara grup eksperimen dan
grup kontrol. Kesembuhan sempurna diperoleh sebanyak 52 kasus (53,6%) pada HCQ dan 6
kasus (6,1%) mengalami kematian. Pada grup kontrol, 33 pasien (34,0%) sembuh total
sedangkan 5 pasien (5,1%) meninggal

0,054
RR lama recovery = = 1,59
0,034

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Critical Appraisal for Therapy Articles

0,061
RR kematian = = 1,20
0,051

Penggunaan HCQ meningkatkan kesembuhan total pasien (RR >1) namun juga meningkatkan risiko
kematian (RR<1)

Absolute Risk Reduction (ARR) = The absolute risk reduction tells us the absolute difference
risk of the outcome in the control in the rates of events between the two groups and gives an
group - risk of the outcome in the indication of the baseline risk and treatment effect. An ARR
treatment group. This is also of 0 means that there is no difference between the two
known as the absolute risk groups thus, the treatment had no effect.
difference.

In our example, the ARR = 0.15 - The absolute benefit of treatment is a 5% reduction in the
0.10 = 0.05 or 5% death rate.

This paper:
ARR Mechanical Ventilator = |0,052 - 0,041| = 0,011 → 1,1%
ARR Kematian = |0,052 - 0,062| = 0,01 → 1%

Manfaat absolut dari pemberian HCQ pada pasien Covid-19 adalah penurunan sebesar 1,1% pada
kebutuhan Mechanical Ventilator.
Risiko absolut dari pemberian HCQ pada pasien Covid-19 adalah peningkatan sebesar 1% pada
resiko kematian yang membutuhkan ventilator.

ARR 28 days recovery = |0,054 - 0,034| = 0,02 → 2%

ARR Kematian = |0,051 - 0,061| = 0,01 → 1%

Manfaat absolut dari pemberian HCQ pada pasien Covid-19 adalah peningkatan sebesar 2% pada
tingkat kesembuhan pasien
Risiko absolut dari pemberian HCQ pada pasien Covid-19 adalah peningkatan sebesar 1% pada
resiko kematian.
Relative Risk Reduction (RRR) = The relative risk reduction is the complement of the RR and
absolute risk reduction / risk of the is probably the most commonly reported measure of
outcome in the control group. An treatment effects. It tells us the reduction in the rate of the
alternative way to calculate the outcome in the treatment group relative to that in the
RRR is to subtract the RR from 1 control group.
(e.g., RRR = 1 - RR)

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Critical Appraisal for Therapy Articles

In our example, the RRR = The treatment reduced the risk of death by 33% relative to
0.05/0.15 = 0.33 or 33% that occurring in the control group.
Or
RRR = 1 - 0.67 = 0.33 or 33%

This paper:
RRR Mechanical Ventilator = |1 - 0,79| = 0,21 atau 21%
RRR Kematian = |1 - 1,19| = 0,19 atau 19%

Pemberian HCQ pada pasien Covid-19 menurunkan penggunaan mechanical ventilator relatif
sebesar 21% terhadap grup kontrol.

Pemberian HCQ pada pasien Covid-19 meningkatkan resiko kematian relatif sebesar 19% terhadap
grup kontrol.

RRR 28 days recovery = |1 - 1,59| = 0,58 atau 58%

RRR Kematian = |1 - 1,2| = 0,2 atau 20%

Pemberian HCQ pada pasien Covid-19 meningkatkan tingkat recovery total relatif sebesar 58%
terhadap grup kontrol.

Pemberian HCQ pada pasien Covid-19 menigkatkan resiko kematian relatif sebesar 20% terhadap
grup kontrol.

Number Needed to Treat (NNT) = The number needed to treat represents the number of
inverse of the ARR and is patients we need to treat with the experimental therapy in
calculated as 1 / ARR. 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 We would need to treat 20 people for 2 years in order to
= 20 prevent 1 death.

This paper:
NNT 28 days recovery = 1/0,02 = 50
NNT Mechanical Ventilator = 1/0,011 = 91
NNT Kematian = 1/0,01 = 100

Dibutuhkan perawatan untuk 50 orang dalam 28 hari untuk meningkatkan kesembuhan 1 pasien
dalam 28 hari.
Dibutuhkan perawatan untuk 91 orang dalam 28 hari untuk mencegah penggunaan 1 mechanical
ventilator.
Dibutuhkan perawatan untuk 100 orang dalam 28 hari untuk mencegah 1 kematian.
2. How precise was the estimate of the treatment effect?

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Critical Appraisal for Therapy Articles

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.

This paper:

Estimasi efek pemberian HCQ pada Pasien Covid-19 dalam menurunkan resiko kematian presisi
karena ARR 0,01 memiliki rentang 95% CI yang cukup sempit (0,243-2,797). Namun tidak presisi
karena rentang 95% CI tersebut melewati angka 0 (0,243-2,797).

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Critical Appraisal for Therapy Articles

Will the results help me in caring for my patient? (External Validity/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?
This paper:
Pasien dalam skenario ini tidak memiliki perbedaan yang signifikan, terutama penggunaan
ventilasi dan tingkat kematiannya sehingga paper ini cocok sebagai EBM dalam memberikan
treatment ke pasien. Walaupun studinya berada di luar negeri, namun variabel penelitian di
Mesir dapat diterapkan di Indonesia

● Is the treatment feasible in my setting?

This paper:
Hasil terapi yang telah ditetapkan pada paper layak untuk terapi pasien, mengingat saat ini
kasus COVID-19 belum memiliki terapi farmakologi yang terstandar sehingga hasil dari jurnal
ini layak untuk dipertimbangkan

● Will the potential benefits of treatment outweigh the potential harms of treatment for my
patient?
This paper:
karena hasil penelitian memiliki profil high reward high risk, disarankan tetap menggunakan
perawatan standar daripada perawatan HCQ karena HCQ tidak terlalu memberikan pengaruh
signifikan dalam treatment, terlebih lagi di jurnal ini disebutkan bahwa HCQ tidak efektif saat
profilaksis pasca pemaparan untuk menangani COVID-19 setelah 4 hari pemaparan

Conclusion

Tetap menggunakan perawatan standar, walaupun pemberian HCQ memberikan tingkat

kesembuhan tinggi, namun profil risikonya tinggi, mempertimbangkan pasien yang rentan
COVID-19 rata-rata adalah lanjut usia dan pasien komorbid yang juga meningkatkan risiko
kematian.

***

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