Effectiveness and Safety of Combination Drug Therapy in Covid-19 patients admitted in a Designated Covid Hospital

Abstract

Background: The corona virus disease (COVID-19) caused by the severe acute respiratory syndrome coronavirus 2

Full text

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Effectiveness and Safety of Combination Drug Therapy in
Covid-19 patients admitted in a Designated Covid Hospital
Dr Sabeena Kizhedath1, Dr Sreelakshmi Venugopal2, Dr Sanal Kumar Kondarappassery Balakumaran3, Dr
Dhanya Sasidharan Palappallil1, Dr Krishnadas Tharemmal Vadakekudilil4,Dr JB Mon5
1Department of Pharmacology, GMC Kottayam, Kerala
2Department of Pharmacology, Pushpagiri Institute of Medical Science and Research Centre, Kerala
3 Department of Pharmacology, GMC Manjeri, Kerala
4Conusltant Physician, GH Tirur,Kerala
5Assistant Surgeon, PHC, Vanimel
Corresponding contributor:
Dr.Dhanya S Palappallil, Associate Professor (CAP), Department of Pharmacology, Govt Medical College, Kottayam
E-mail –drspdhanya@gmail.com
Abstract
Background: The corona virus disease (COVID-19) caused by the severe acute respiratory syndrome coronavirus 2
(SARS CoV-2) virus has affected the whole world. Researches are on-going in search of effective and safe drugs. The
first wave of the pandemic was managed with some repurposed drugs and some newer antiviral drugs. There is limited
data on the effectiveness and safety of these drugs. Our study was done to determine the effectiveness and safety of
drugs used as combination in COVID 19 infection.
Methods: This was a descriptive record-based study done in a tertiary care COVID hospital in Manjeri of Malappuram
district in Kerala from 1st March 2020 to 30th November 2020. Demographic details, comorbidities, lab investigations,
treatment measures and medications on admission till discharge, adverse effects & outcomes were taken from medical
records. The severity assessment was obtained from World Health Organisation (WHO) Ordinal Scale and outcome
assessment was based on the number of days taken for a 2-point step down from the WHO ordinal scale. Data were
entered into Excel sheet and analysed using SPSS. The effectiveness of combination was determined using independent
t test.
Results: Of the 200 patients, majority received Hydroxychloroquine (n=125) and Azithromycin(n=192). The other
drugs prescribed were anticoagulants, monoclonal antibodies, steroids and convalescent plasma. All the patients in
Category B had WHO ordinal scale of 3 while majority 97(59.9%) in Category C had an ordinal Scale of 4. The oxygen
mask days and mean WHO 2 step down days were lower in the 45 patients who received Remdesivir with
anticoagulation. The common adverse effects observed were were hematuria 17(8.5%), new onset diabetes mellitus
14(7%), diarrhoea 5(2.5%) and hypoglycemia 2(1%).
Conclusion: The majority of patients received Hydroxychloroquine and Azithromycin with or without Anticoagulants,
Corticosteroids, Antiviral drugs, Monoclonal antibodies and Convalescent plasma according to severity of disease. The

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combination of Remdesivir with Anticoagulation was found to reduce the severity grade of COVID 19 infection faster
compared to Anticoagulation alone and those without Remdesivir in Category C patients.
Keywords: COVID, Remdesivir, Hydroxychloroquine, WHO Ordinal Scale, Anticoagulation
INTRODUCTION
SARS-CoV-2 infection is a wide spectrum disease which encompass asymptomatic infections, mild upper respiratory
tract illness, and severe viral pneumonia with respiratory failure and even death.1 In India, the first laboratory-confirmed
case of COVID-19 was reported from Kerala on January 30, 2020.2 The COVID-19 has resulted in the deaths of more
than 68,73,477 persons worldwide as of March 16, 2023.3
Currently several studies have discussed the therapeutics for COVID-19, including repurposing of medications. Based
on evidence on the suppression of activity, hydroxychloroquine was used along with azithromycin for the treatment.4
Different mechanisms like blockade of viral entry into cells by inhibiting glycosylation of host receptors,
immunomodulatory effects, inhibition of autophagy and lysosomal activity in host cells has led to the use of
hydroxychloroquine. Azithromycin was thought to interferes with cleavage of the spike protein, preventing viral entry
into host cells. 5 More antiviral drugs, anticoagulants, corticosteroids and plasma therapy were added as the treatment
for the disease evolved. This study was done to determine the effectiveness and safety of combination drug therapy in
COVID 19 patients admitted in a tertiary care centre which was designated as a COVID hospital during the initial year
of the pandemic.
MATERIALS AND METHODS
This was a record based descriptive study done in a designated COVID hospital of Malappuram district in North Kerala
after obtaining Institutional Ethics Committee Clearance. Case record files of patients >18 years of any gender,
admitted in the medicine department from 1st March 2020 to 30th November 2020 and confirmed as COVID 19 positive
by Reverse Transcriptase Polymerase Chain Reaction (RT-PCR) were included in the study. Pregnant ladies, lactating
mothers, patients with hepatic impairment, Human Immunodeficiency Virus patients, allergy to any of the drugs
included in the study and incomplete medical records were eliminated from the study. Retrospective evaluation of case
sheets of all admitted patients diagnosed to have COVID19 in medicine ward was done. Patient demographics, pre-
existing conditions, lab investigations, clinical measures and medications on admission till discharge, adverse events &
outcomes were abstracted from medical records. The data recorded were compared across age groups (18-40, 40-60 and
above 60 years), gender and patients with or without comorbidities. Data were entered into Excel sheet and analysed
using SPSS. The parameter considered for monitoring outcome was WHO Ordinal Scale which is a “9 points scale- 0:
no clinical or virological evidence of infection; 1: ambulatory, no activity limitation; 2: ambulatory, activity limitation;
3: hospitalized, no oxygen therapy; 4: hospitalized, oxygen mask or nasal prongs; 5: hospitalized, non-invasive
mechanical ventilation (NIMV) or high-flow nasal cannula (HFNC); 6: hospitalized, intubation and invasive
mechanical ventilation (IMV); 7: hospitalized, IMV + additional support such as pressors or extracardiac membranous
oxygenation (ECMO); 8: death”.6 The patients were categorized into B and C based on the guidelines released by the
Ministry of Health and Family Welfare, Government of Kerala.7 Quantitative variables were expressed as mean ±
standard deviation, qualitative variables were expressed as frequencies and percentage. Independent t test was done to
determine the difference in the outcome in Category B and C patients.

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Results
A total of 200 patients who were admitted in the study centre were recruited for the study. The mean age was
51.4±17.63 years with minimum age 18, maximum age 91 years. Majority were in the age group 18-40 years
[73(36.5%)] followed by >60 years [65 (32.5%)] and 40-60 years [62 (31%)]. Out of the 200 patients, 136(68%) were
males and 64(32%) were females. There was atleast one associated comorbidity in 116 (58%) patients which were
diabetes, hypertension, dyslipidemia, ischemic heart disease, cerebrovascular accident, renal or hepatic dysfunction.
Table 1: Baseline characteristics of the patients
Males N(%)
Females N(%)
Age in years
18-40(N=73)
40-60(N=62)
>60 years(N=65)
51(69.9)
46 (74.2)
39 (0.6)
22 (20.1)
16 (25.8)
26 (0.4)
Associated Comorbidities (N=116)
70 (60.3)
46 (39.7)
Hypertension (N=66)
38(57.6)
28(42.4)
Diabetes Mellitus(N=85)
51(60.0)
34(40.0)
Ischemic Heart Disease(N-61)
44(72.1)
17(27.9)
Dyslipidaemia(N=17)
11(64.7)
6(35.3)
Cerebrovascular Accident(N=13)
4(30.8)
9(69.2)
Renal Disease(N=13)
9(69.2)
4(30.8)
Hepatic Disease(N=18)
11(61.1)
7(38.9)
Of the total 200 patients, 38(19%) were Category B and 162(81%) were category C. Seventy-Nine patients (39.5%)
developed changes in Chest X ray of which 7 had cardiomegaly, 62 bilateral infiltrates, 4 unilateral infiltrates, 4 pleural
effusion and 2 pulmonary fibrosis. The details of patients who received various antimicrobial drugs is summarised in
Table 2
Table 2: Details of Antimicrobial Therapy
Drugs
Category B
N(%)
Category C
N(%)
Hydroxychloroquine(N=125)
30 (24)
95(76)
Lopinavir/Ritonavir(N=2)
0
2(100)
Piperacillin-Tazobactam(N=43)
1(2.3)
42(97.7)
Azithromycin(N=192)
37(19.3)
155(80.7)
Amoxicillin-Clavulanic Acid(N=6)
1(16.7)
5(83.3)
Favipiravir(N=22)
1(4.5)
21(95.5)
Remdesivir(N=47)
2(4.3)
45(93.7)

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Of the 200 patients majority received Hydroxychloroquine (HCQ) (n=125) and azithromycin(n=192) as shown in Table
2. The other drugs prescribed were anticoagulants (n=93), monoclonal antibodies (n=7), steroids(n=91) and
convalescent plasma (n=32).
Table 3 summarizes the various combinations of drugs used in patients who received HCQ with other antiviral drugs
like lopinavir, favipiravir and remdesivir, antibiotics like azithromycin as well as amoxicillin and clavulanic acid,
anticoagulants, steroids and plasma. The table also depicts the mortality, Lactate Dehydrogenase (LDH) values, d-dimer
and Ferritin at admission and at discharge. As shown in Table 3, out of the 125 patients who received
hydroxychloroquine, among Category B patients, 29 received azithromycin, 1 amoxicillin + clavulanic acid, 10 steroids
and 3 plasma as combinations. The antivirals and anticoagulants were given as combination along with HCQ only in the
Category C patients. Out of the 24 patients who received anticoagulants with HCQ, the D-dimer was elevated in 19
patients at the time of admission and it was still elevated in 16 patients at the time of discharge.
Table 3: Combination Therapy in patients who received Hydroxychloroquine
Hydroxychl
oroquine
Category
Lopi
navir
/
Rito
navir
[N=2
]
Favipi
ravir
[N=1]
Remde
sivir
[N=12]
Azithro
mycin
[N=121]
Amoxic
illin-
Clavula
nic
Acid[N
=6]
Piperaci
llin-
Tazoba
ctam
[N=17]
Anticoag
ulant
[N=24]
Monocl
onal
Antibod
y
[N=7}
Steroi
ds
Plasm
a
Category
B
0
0
0
29
(24)
1
(16.7)
0
0
0
10
(41.7)
3(23.1
)
C
2
(100
)
1
(100)
12
(100)
92
(76)
5
(83.3)
17
(100)
24
(100)
7
(100)
14
(58.3)
10
(76.9)
Mortality
Alive
1
(50)
1
(100)
12
(100)
118
(97.5)
6
(100)
14
(82.3)
21
(87.5)
7
(100)
10
(41.7)
3
(23.1)
Dead
1
(50)
0
0
3
(2.5)
0
3
(17.6)
3
(12.5)
0
14
(58.3)
10
(76.9)
D-Dimer at
admission
Normal
0
0
2
(11.8)
85
(70.2)
1
(16.7)
2
(11.8)
5
(20.8)
1
(14.3)
10
(41.7)
3
(23.1)
Elevated
2
(100
)
1
(100)
15
(88.2)
36
(29.8)
5
(83.3)
15
(88.2)
19
(79.2)
6
(85.7)
14
(58.3)
10
(76.9)
D-Dimer
at discharge
Normal
1
(50)
0
5
(41.7)
96
(79.3)
2
(33.3)
6
(35.3)
8
(33.3)
3
(42.9)
14
(58.3)
5
(38.5)
Elevated
1
(50)
1
(100)
7
(58.3)
25
(20.7)
4
(66.7)
11
(64.7)
16
(66.7)
4
(57.1)
10
(41.7)
8
(61.5)
Ferritin at
admission
Normal
1
(50)
0
3
(25)
96
(79.3)
1
(16.7)
5
(29.4)
6
(25)
1
(14.3)
11
(45.8)
3
(23.1)

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Elevated
1
(50)
1
(100)
9
(75)
25
(20.7)
5
(83.3)
12
(70.6)
18
(75)
6
(85.7)
13
(54.2)
10
(76.9)
Ferritin at
Discharge
Normal
1
(50)
0
5
(41.7)
100
(82.6)
2
(33.3)
5
(29.4)
7
(29.2)
2
(28.6)
13
(54.2)
5
(38.5)
Elevated
1
(50)
1
(100)
7
58.3%
21
(17.4)
4
(66.7)
12
(70.6)
17
(70.8)
5
(71.4)
11
(45.8)
8
(61.5)
LDH at
admission
Normal
2
(100
)
0
3
(25)
92
(76)
2
(33.3)
4
(23.5)
7
(29.2)
1
(14.3)
10
(41.7)
3
(23.1)
Elevated
0
1
(100)
9
(75)
29
(24)
4
(66.7)
13
(76.5)
17
(70.8)
6
(85.7)
14
(58.3)
10
(76.9)
LDH at
discharge
Normal
2
(100
)
0
4
(33.3)
101
(83.5)
3
(50)
6
(35.3)
10
(41.7)
1
(14.3)
11
(45.8)
4
(30.8)
Elevated
0
1
(100)
8
(66.7)
20
(16.5)
3
(50)
11
(64.7)
14
(58.3)
6
(85.7)
13
(54.2)
9
(69.2)
Fig 1: Baseline WHO Ordinal Scale
As shown in Fig 1, at baseline all the patients in Category B had WHO ordinal scale of 3 (hospitalized, no oxygen
therapy) while majority 97(59.9%) in Category C had an ordinal Scale of 4 (hospitalized, oxygen mask or nasal prongs).
After the initiation of the combination therapy the outcome was measured by the number of days taken to achieve a 2-
point step down from the WHO ordinal scale.
38 41
97
24
0
20
40
60
80
100
120
Scale 3 Scale 4 Scale 5
Baseline WHO Ordinal Scale
Category B Category C

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Table 4: Outcome based on Category of patients
Outcome
Category B
Category C
p Value (95% CI of
difference)
Mean Hospital Days
9.47 ± 3.4
13.28 ± 7.03
0.001(-6.12 - -1.48)
Mean Intensive Care Unit Days
0.11± 0.65
3.90 ± 6.21
<0.001(-5.8- -1.8)
Mean Oxygen Days
4.29±3.68
5.30 ± 4.26
0.181(-2.48 -0.47)
Mean Non-Re Breathing Mask days
0.13± 0.67
1.62 ± 2.96
0.003(-2.44 - -0.53)
Mean High Flow Oxygen Days
0.11± 0.65
1.97 ± 4.16
0.007(-3.2 - -0.52)
Mean Non-Invasive Mechanical Ventilation Days
0
1.67±3.45
0.003(-2.77- -0.56)
Mean WHO 2 step down days
5.95± 2.7
8.17± 6.76
0.049 (-3.58- -0.86)
Out of the 200 patients, 30 patients died and 6 required mechanical ventilation. Table 4 summarizes the outcome based
on Category of patients. As evident, there was statistically significant difference in all except the mean oxygen days.
The mean WHO 2 step down days was higher in the Category C as compared to Category B. As shown in Figure 2, the
WHO 2 step down days were <10 days for 35 patients (92.1%) in Category B and 97 patients (59.9%) in Category C.
Only 6 patients and one patient in Category C required more than 20 days and 30 days respectively for achieving two
step downs in the WHO ordinal scale. There was no statistically significant difference in the achievement of two step
downs of the WHO ordinal scale gender wise(p=0.74) , age wise(p=0.9) and based on the presence of co-
morbidities(p=0.43)
Fig 2: WHO 2 Step Down Days
35
3
67
58
61
0
10
20
30
40
50
60
70
80
<10 days 10-20 days 21-30 days 31-40 days
Number of patients
WHO 2 Step Down Days
Category B category C

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Table 5: Outcomes in patients without Remdesivir, anticoagulation without Remdesivir and Anticoagulation with
Remdesivir in Category C patient
Multiple
Combinations
Without
Remdesivir*
(n=117)
With Remdesivir
and
Anticoagulation
(n=45)
p (95% Confidence
Interval)
Anticoagulation
without Remdesivir $
(n=43)
p (95% Confidence
Interval)
Mean
Std.
Deviatio
n
Mean
Std.
Deviatio
n
Mean
Std.
Deviatio
n
Hospital days
12.53
6.419
15.22
8.196
0.029(-5.1 - -0.28)
13.84
7.761
0.42(-4.7- -2)
Ferritin at Discharge
401.20
362.706
742.58
582.855
<0.001(-491 - -190.8)
662.53
473.506
0.48(113.5- -305.69)
LDH at discharge
344.62
356.399
712.44
617.475
<0.001(-521- -214)
606.19
450.321
0.36(115.6- -336.16)
ICU days
1.50
3.221
10.13
7.677
<0.001(-10.31- -6.94)
3.84
4.225
<0.001(-8.9- -3.6)
Oxygen days
6.43
4.316
2.36
2.238
<0.001(3.04 -5.1)
5.53
4.621
<0.001(1.65-4.7)
NRBM days
1.25
2.849
2.58
3.086
0.14(-2.14- -0.28)
2.60
3.717
0.97(-1.4- -1.4)
High Flow Oxygen
days
.79
2.169
5.04
6.135
<0.001(-6,14 - -2.37)
1.93
2.995
0.003(-5.1- -1.1)
NIMV
.62
2.113
4.40
4.594
<0.001(-5.2- -2.3)
1.56
3.254
0.001(-4.5- -1.1)
IMV days
.09
.557
.09
.468
0.95(-0.16- 0.17)
.26
.902
0.28(-4.4- -1.1)
Mean WHO 2 step
down days
8.07
5.846
7.35
9.167
0.56(-2.39- 3.8)
7.62
7.199
0.88(-3.4-3.9)
*Total Category C patients is 162 of which 45 received Remdesivir and 117 did not receive Remdesivir
$Total Category C patients who received anticoagulation is 88 of which 45 received it with Remdesivir, while
43 received anticoagulation alone without Remdesivir
As shown in Table 5, the mean was higher in the 45 patients who received Remdesivir as compared to other
combinations for hospital stay, Intensive Care Unit days, Ferritin and LDH at discharge, NRBM, High flow oxygen,
NIMV days whereas the oxygen days and mean WHO 2 step down days were lower. Out of the 88 patients who
received anticoagulation among Category C patients, 76 received steroids. Of the 45 patients who received Remdesivir
all received anticoagulation, 42 received steroids, 26 received convalescent plasma and 7 received monoclonal
antibodies. While comparing the 88 patients who received anticoagulation with and without Remdesivir, the mean
Oxygen days, NRBM days and WHO 2 step down days were lower in those who received remdesivir with
anticoagulation.

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Fig 3: Medication use in participants who died of COVID
As shown in Fgure 3, of the 30 participants who succumbed to COVID majority of them had received
anticoagulants(29), steroids(26), azithromycin (25). Seven received plasma, 4 received favipiravir,1 received
Lopinavir/Ritonavir, 2 HCQ and 18 received remdesivir.
The common adverse reactions encountered in the patients were diarrhoea 5(2.5%), hypoglycemia 2(1%), new onset
diabetes mellitus 14(7%). Oral hypoglycemics were changed over to Insulin in 66(33%) and the insulin dose was
escalated in 19(9.5%). Hematuria was observed in 17(8.5%). In the patients who complained of diarrhoea the suspected
drug was azithromycin. Those who developed new onset diabetes were on steroids and those who developed hematuria
had anticoagulants.
Discussion
Coronavirus disease 2019 (COVID-19), first identified in the China Wuhan of the Hubei Province is now called severe
acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and was declared a pandemic in January 2020.8 For the
treatment of COVID 19 many drugs were repurposed and used, of which HCQ was among the firsts, however the
proof of the clinical benefit was not proven. Numerous antivirals and immunotherapies were adopted and still continue
to be tested.8 The interim guidelines for the treatment of COVID patients was released by the Government of Kerala in
March 2020 and the second version was released in August 2020.7,9 This study was conducted during the initial year of
COVID and hence explores the effectiveness of the combinations of drugs used and the adverse effects attributed to
these drugs in a designated COVID hospital. The Kerala model for combating COVID 19 was discussed and accepted
worldwide for adopting the World Health Organisation’s test, trace, isolate and treat policy.10
The mean age of the participants was 51.4±17.63 years and the male: female ratio was 2.1: 1. Jaya et al., describing the
epidemiology of COVID 19 pandemic in Kerala states that of those affected in Kerala, males were 51.7%, females were
46.1% and transgenders 2.2%. Majority were in the age group 21-40 followed by 41.60 years.11 In similar studies done
27
29
26
12
5
11
4
1
23
3
1
4
18
25
19
26
29
7
0 5 10 15 20 25 30
Hydroxychloroquine
Lopinavir/Ritonavir
Favipiravir
Remdesivir
Azithromycin
Piperacillin+Tazobactam
Steroids
Anticoagulants
Plasma
Medication Use in Patients who died
No Yes

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elsewhere, the majority of the participants were in the age group 41-60 years and males were more than females which
is comparable to ours.12–14 The guidelines that existed during the time of study had identified the risk of getting COVID
19 infection in patients based on the level of comorbidities and in this study we identified 58% patients with associated
comorbidities.7
Hydroxychloroquine 400 mg orally twice daily on the first day followed by 200mg twice daily for the next 4 days
along with azithromycin 500 mg orally (Intravenous stat for Category C) on Day 1 and 250 mg for the next 4 days was
recommended by the interim guideline for Category B and C patients.7 Addition of favipiravir 1800mg orally for two
doses then 800mg twice daily for total 7 to 10 days instead of azithromycin or the use of Tablets Lopinavir / Ritonavir
(400/100) twice daily for 14 days or for 7 days after becoming asymptomatic were recommended in the revised Version
2 released in August 2020.9 It also recommended the use injection remdesivir 200 mg IV on day 1 followed by 100 mg
IV daily for total 5 days If duration of symptoms is less than 10 days along with steroids, convalescent plasma and
anticoagulation. In this study out of the 200 patients 125 received hydroxychloroquine and 121 received azithromycin.
As shown in table 3, out of the 38 category B patients, 29 received azithromycin, 1 received amoxicillin + clavulanic
acid , 10 received steroids and three convalescent plasma along with hydroxycloroquine. In the Category C,
hydroxychloroquine was combined with atleast one of these drugs i.e., Lopinavir/Ritonavor (2), favipiravir (1),
remdesivir (12), azithromycin (121), pipercaillin+ tazobactam (17), anticoagulants (24), monoclonal antibody (7),
steroids (14) and convalescent plasma (10). The latest guideline of Ministry of Health and Welfare, Government of
Kerala released in April 2021 however doesn’t recommends use of hydroxychloroquine and azithromycin in Category B
or C replacing it with oral ivermectin 200mcg/kg/day (not exceeding 12mg) daily for 3-5 days in both categories. The
latest guideline also retained the use of favipiravir and remdesivir in Category C. 15
The therapeutic approaches in COVID 19 include treatment with antiviral drugs (favipiravir, remdesivir), anti-
inflammatory agents (dexamethasone, hydroxychloroquine), and immuno-modulators. Currently, combination treatment
of remdesivir with dexamethasone and immune therapies, is considered the optimal treatment strategy. 16 Studies
analysing the prescription pattern in COVID 19 elsewhere state that corticosteroids, anticoagulants, colchicine as well
as azithromycin, ivermectin, and hydroxychloroquine were frequently prescribed.12,14 A study done in Germany states
that remdesivir was used in 31.3% , corticosteroids in 61.7%, and monoclonal antibodies in 2.3%. Dexamethasone
combined with remdesivir administration was the most common therapeutic approach during the second pandemic
wave while corticosteroids predominated during the third wave with a significant lower mortality with the
combination.17
From Table 2 , its is evident that out of the 200 patients, 192 received azithromycin; so 67 patients who didn’t receive
hydroxycloroquine received azithromycin. Favipiravir was initiated in 1 Category B and 20 Category C patients and
remedesivir was prescribed for 2 Category B and 34 Category C patients without combining with hydroxychloroquine.
In a multi-hospital assessment, treatment with hydroxychloroquine alone and in combination with azithromycin was
found to reduce COVID-19 associated mortality.4 However a review by Alam et al., points out several articles that
shows that the effect of hydroxychloroquine is inconclusive even though it was widely used because of the easy
availability at the start of the pandemic.18A rapid review on the use of azithromycin says that there is little evidence that
warrants the use of azithromycin for the treatment of COVID-19 unless there is bacterial super-infection. There is an
equally negative evidence depicting possible synergy between azithromycin and hydroxychloroquine.5

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Coppock et al., evaluating the effect of combinations and its association with mortality in a large multisite health care
system found that the use of anticoagulation alone was solely associated with decreased mortality in patients admitted
in the Intensive Care Units. In addition the combinations of anticoagulation with remdesivir, corticosteroids and both
were associated with lower mortality.19 In this study, a higher mean was obtained in the Category C patients who
received a combination of remdesivir and anticoagulation for total hospital days, Intensive Care Unit days, Non
Invasive Ventilation days and the values of ferritin and LDH at the time of discharge. This could be due to the fact that
these combinations were given in patients who were more critical. It is noticeable that the mean 2 step down of the
WHO ordinal scale and the oxygen days were lower in these patients.Sahai et al., states that regular screening of
coagulation profile and anticoagulant therapy should be started early ias per the standard guidelines so that
comlications of COVID can be avoided.20 The WHO severity scale has been a good classifying and predictive tool for
COVID 19 outcome measurement. However the limitations of the tool includes its inability to classify patients based on
the criticality of oxygen requirements.6
Remdesivir and Favipiravir inhibits the RNA-dependent RNA polymerase and has shown its efficacy against SARS-
CoV-1 through the improvement of lung infection.12,21 In their review Hossain et al., points out several studies which
demotes that early treatment with this drug shorten recovery and discharge time and it has good safety and good
tolerability.21 Terada et al., found that the combination of favipiravir, camostat and ciclesonide decreases hospital days
without safety concerns.22 However Hossain et al., pointed out that HCQ has a bad safety profile as compared to
remdesivir.21 We did not record any adverse events suspected due to the antivirals. The observed adverse effects
included azithromycin induced diarrhoea , steroid induced diabetes mellitus and hematuria due to anticoagulation. A
review on the safety of drugs used during the first covid wave showed that the most frequent adverse reactions were
gastrointestinal and the drugs more frequently involved included Lopinavir/ritonavir ,hydroxychloroquine and
azithromycin.23
Limitations of this study include that it was a single centre study and was restricted to the first pandemic wave. The
WHO ordinal scale step down used for outcome measurement has some drawbacks in the classification of patients.
Conclusion
Our study puts forward an analysis regarding the effectiveness and safety of combination of drugs during the first wave
of COVID 19 pandemic. The majority of patients received Hydroxychloroquine and Azithromycin with or without
Anticoagulants, Corticosteroids, Antiviral drugs, Monoclonal antibodies and Convalescent plasma according to severity
of disease. The combination of Remdesivir with Anticoagulation was found to reduce the severity grade of COVID 19
infection faster compared to Anticoagulation alone and those without Remdesivir in Category C patients. Even though
there is no conclusive evidence showing the efficacy of Hydroxychloroquine and Azithromycin in COVID 19 infection,
these were very commonly used during the first wave of pandemic. Anticoagulant induced hematuria and Corticosteroid
induced hyperglycemia were the the commonest adverse effects observed during the course of treatment. Most of the
adverse effects were mild to moderately severe and largely self limiting; but, we suggest follow up of the patients to
know about the sequelae due to the disease as well as drugs.
Sources of Funding-Nil
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