1. Epidemiology and Global Health
  2. Microbiology and Infectious Disease
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Identification of drugs associated with reduced severity of COVID-19 – a case-control study in a large population

  1. Ariel Israel  Is a corresponding author
  2. Alejandro A Schäffer
  3. Assi Cicurel
  4. Kuoyuan Cheng
  5. Sanju Sinha
  6. Eyal Schiff
  7. Ilan Feldhamer
  8. Ameer Tal
  9. Gil Lavie
  10. Eytan Ruppin  Is a corresponding author
  1. Division of Planning and Strategy, Clalit Health Services, Israel
  2. Cancer Data Science Laboratory, National Cancer Institute, National Institutes of Health, United States
  3. Clalit Health Services, Southern District and Faculty of Health Sciences, Ben-Gurion University of the Negev, Israel
  4. Sheba Medical Center, Tel-Aviv University, Israel
  5. Ruth and Bruce Rappaport Faculty of Medicine, Technion – Israel Institute of Technology, Israel
Research Article
Cite this article as: eLife 2021;10:e68165 doi: 10.7554/eLife.68165
2 figures, 2 tables and 3 additional files

Figures

Histogram showing the distribution of the odd ratios (OR) of medication use with the outcome in cohorts 1 and 2.

The overwhelming majority of medications are associated with neutral effect (gray) or increased risk for hospitalization (black, OR>1), only a few are associated with significantly decreased risk (black, OR<1).

Ubiquinone and cholesterol biosynthesis pathway.

Ubiquinone and cholesterol biosynthesis pathways originate from a branching of the mevalonate pathway at FPP. Rosuvastatin and other statins can inhibit the HMG-CoA reductase, while risedronic acid and other bisphosphonates can inhibit the FPP synthase. Ac-CoA: acetyl coenzyme A, HMG-CoA: hydroxymethylglutaryl coenzyme A, GPP: geranyl pyrophosphate, FPP: farnesyl pyrophosphate, PPP: polyprenyl pyrophosphate.

Tables

Table 1
Demographics and clinical characteristics of the two matched cohorts of patients (hospitalized versus non-hospitalized).
Cohort 1Cohort 2
COVID-19 hospitalized (cases)Not hospitalized
(controls)
COVID-19 hospitalized (cases)Not hospitalized
(controls)
n653032,650695313,906
Age (mean, SD)64.6 (16.1)64.8 (15.8)65.7 (16.0)65.7 (15.8)
Sex, female (%)3259 (49.9)16,295 (49.9)3381 (48.6)6762 (48.6)
Hospitalization severity (n, %)
Mild condition3008 (46.1)2676 (38.5)
Serious condition851 (13.0)1043 (15.0)
Severe condition1621 (24.8)1903 (27.4)
Deceased1050 (16.1)1331 (19.1)
Smoking status (%)
Never smoker5012 (76.8)24,218 (74.2)5156 (74.2)10,312 (74.2)
Past smoker1115 (17.1)5808 (17.8)1338 (19.2)2676 (19.2)
Current smoker403 (6.2)2624 (8.0)459 (6.6)918 (6.6)
Nb visits at primary doctor in last year (mean, SD)8.1 (7.9)7.9 (7.3)8.2 (8.4)7.5 (7.1)
Comorbidity (%)
Arrhythmia887 (13.6)4242 (13.0)1278 (18.4)2221 (16.0)
Asthma527 (8.1)2941 (9.0)650 (9.3)1376 (9.9)
Congestive heart failure (CHF)228 (3.5)1140 (3.5)784 (11.3)851 (6.1)
Chronic obstructive pulmonary disease (COPD)148 (2.3)740 (2.3)603 (8.7)776 (5.6)
Diabetes2976 (45.6)14,880 (45.6)3425 (49.3)5549 (39.9)
Hypertension3850 (59.0)19,062 (58.4)4396 (63.2)8102 (58.3)
Ischemic heart disease (IHD)1464 (22.4)7320 (22.4)1838 (26.4)3113 (22.4)
Malignancy1087 (16.6)5435 (16.6)1280 (18.4)2766 (19.9)
Chronic kidney disease (CKD)102 (1.6)510 (1.6)1086 (15.6)1117 (8.0)
Obesity (documented diagnosis)3761 (57.6)17,837 (54.6)3975 (57.2)7950 (57.2)
Body mass index (BMI) (mean, SD)28.7 (5.7)28.6 (6.5)29.1 (6.3)28.5 (5.7)
BMI group (%)
<18.517 (0.3)85 (0.3)51 (0.7)93 (0.7)
18.5 to 251070 (16.4)5350 (16.4)1244 (17.9)2471 (17.8)
25 to 302295 (35.1)11,475 (35.1)2264 (32.6)4870 (35.0)
30 to 352053 (31.4)10,265 (31.4)2005 (28.8)4267 (30.7)
35 to 40761 (11.7)3805 (11.7)886 (12.7)1562 (11.2)
>40334 (5.1)1670 (5.1)503 (7.2)643 (4.6)
Glomerular filtration rate (GFR) (mean, SD)85.7 (21.6)85.8 (20.3)78.7 (28.2)83.4 (22.4)
Chronic kidney disease (CKD) staging (n, %)
G13047 (46.7)15,145 (46.4)2837 (40.8)6090 (43.8)
G22679 (41.0)13,747 (42.1)2535 (36.5)5722 (41.1)
G3a558 (8.5)2817 (8.6)689 (9.9)1257 (9.0)
G3b203 (3.1)836 (2.6)391 (5.6)571 (4.1)
G441 (0.6)89 (0.3)186 (2.7)160 (1.2)
G563 (0.9)28 (0.2)
Dialysis2 (0.0)16 (0.0)252 (3.6)78 (0.6)
Table 2
Most significant associations for medications acquired in the 35 days preceding the index date in two matched cohorts.
ATC code and classUse in caseUse in contr.Case %Contr.
%
Odds ratio
(95% conf. int.)
p-ValueFDR
(A) Cohort 1 (N = 6530 hospitalization cases, N=32,650 controls taken from the general population)
C10AA07
Rosuvastatin
32823805.027.290.673 (0.596 to 0.758)<0.0001<0.001
C10AX09
Ezetimibe
737401.122.270.488 (0.377 to 0.622)<0.0001<0.001
A16AX30
Ubiquinone (CoQ-10)
61650.090.510.181 (0.065 to 0.403)<0.0001<0.001
C01BC04
Flecainide
71160.110.360.301 (0.118 to 0.641)0.000390.005
J07AL02
Pneumococcus vaccine conjugate
212200.320.670.476 (0.288 to 0.746)0.000490.006
C09BA05
Ramipril-hydrochlorothiazide
1278591.952.630.734 (0.603 to 0.887)0.000990.011
A10BD07
Sitagliptin-metformin
24315013.724.600.802 (0.696 to 0.922)0.001590.017
C10AA03
Pravastatin
523850.801.180.673 (0.493 to 0.902)0.006590.060
N06AB10
Escitalopram
21613023.313.990.824 (0.708 to 0.955)0.009300.078
M01AC01
Piroxicam
242050.370.630.584 (0.365 to 0.894)0.009800.082
C09CA06
Candesartan
654511.001.380.718 (0.544 to 0.934)0.012370.100
M05BA07
Risedronic acid
563960.861.210.705 (0.522 to 0.935)0.013190.103
G04CB02
Dutasteride
302400.460.740.623 (0.411 to 0.914)0.013670.105
A11CC05
Cholecalciferol
660363410.1111.130.898 (0.821 to 0.980)0.016000.119
C09AA08
Cilazapril
171530.260.470.554 (0.315 to 0.918)0.017430.124
G04BE08
Tadalafil
292290.440.700.632 (0.413 to 0.933)0.018620.132
S01ED61
Timolol-travoprost
8900.120.280.444 (0.186 to 0.913)0.020680.142
A10BH01
Sitagliptin
332500.510.770.658 (0.443 to 0.950)0.024610.162
J07BB02
Influenza vaccine inac
39222056.006.750.882 (0.787 to 0.986)0.025480.165
N06DX02
Ginkgo folium
2420.030.130.238 (0.028 to 0.915)0.025520.165
A12CC04
Magnesium citrate
312370.480.730.652 (0.433 to 0.952)0.025970.166
A10BK01
Dapagliflozin
352550.540.780.685 (0.466 to 0.978)0.032830.193
(B) Cohort 2 (N = 6953 hospitalization cases, N=13,906 controls taken from patients SARS-CoV-2 positive)
C10AA07
Rosuvastatin
3549505.096.830.732 (0.643 to 0.831)<0.00010.000
C10AX09
Ezetimibe
923031.322.180.602 (0.471 to 0.764)0.000010.000
J07AL02
Pneumococcus vaccine conjugate
20950.290.680.419 (0.245 to 0.685)0.000210.003
M05BA07
Risedronic acid
471650.681.190.567 (0.400 to 0.789)0.000420.005
A16AX30
Ubiquinone (CoQ-10)
9560.130.400.321 (0.139 to 0.653)0.000520.006
N06AB10
Escitalopram
2366103.394.390.766 (0.654 to 0.894)0.000610.007
C09BA05
Ramipril-hydrochlorothiazide
1213421.742.460.702 (0.565 to 0.869)0.000820.009
C01BC04
Flecainide
7430.100.310.325 (0.123 to 0.729)0.002530.023
S01XA40
Hydroxypropyl-methylcellulose (tears)
672030.961.460.657 (0.490 to 0.871)0.002730.025
A11CC05
Cholecalciferol
737166910.6012.000.869 (0.792 to 0.954)0.002800.025
B01AE07
Dabigatran etexilate
371240.530.890.595 (0.400 to 0.866)0.005430.042
C09AA08
Cilazapril
15640.220.460.468 (0.247 to 0.831)0.005790.044
N02CC04
Rizatriptan
1170.010.120.118 (0.003 to 0.750)0.010650.075
A12CC04
Magnesium citrate
331080.480.780.609 (0.399 to 0.908)0.011910.080
S01KA01
Hyaluronic acid (artificial tears)
5310.070.220.322 (0.098 to 0.836)0.012490.083
C09DB01
Valsartan-amlodipine
2275493.273.950.821 (0.698 to 0.963)0.014450.094
A10BD07
Sitagliptin-metformin
2335603.354.030.826 (0.704 to 0.967)0.017210.108
B03BA51
Vit.B12 combinations
311000.450.720.618 (0.399 to 0.934)0.019790.119
G03CA03
Estradiol
18670.260.480.536 (0.300 to 0.914)0.020470.122
C09DA01
Losartan-hydrochlorothiazide
1243151.782.270.783 (0.630 to 0.969)0.024240.140
S01ED01
Timolol
20700.290.500.570 (0.328 to 0.949)0.024920.143
G04BD12
Mirabegron
22740.320.530.593 (0.351 to 0.967)0.029980.163
S01XA02
Retinol (eye ointment)
3210.040.150.285 (0.054 to 0.956)0.030150.163
Z01CE01
Eye care wipes
3210.040.150.285 (0.054 to 0.956)0.030150.163
N06AX12
Bupropion
6300.090.220.399 (0.136 to 0.976)0.033850.177
N06BA04
Methylphenidate
8360.120.260.444 (0.178 to 0.972)0.036560.186
A12AX05
Calcium-zinc CD
0100.000.070.000 (0.000 to 0.892)0.036960.186
A11JC02
Multivitamins for ocular use
25810.360.580.616 (0.376 to 0.976)0.038270.191
  1. Numbers are of patients from the group who have acquired a medication from the class in the last month before the index date.

    p-Values are calculated according to Fisher's exact test. Medications are sorted by increasing order of p-values.

  2. OR: odds ratio; [95% CI]: 95% confidence interval; FDR: false discovery rate calculated according to Benjamini-Hochberg (BH) procedure.

    Shown in this table are anatomical therapeutic chemical (ATC) classes for which the p-value is less than 0.05, and for which the FDR is less than 0.20 (about 80% of entries are expected to be true positive).

Additional files

Source code 1

R source code, producing Figure 1.

https://cdn.elifesciences.org/articles/68165/elife-68165-code1-v2.zip
Supplementary file 1

Supplementary tables and figures.

Suppl Tab 1 Multivariable logistic regression for hospitalization status according to ethnicity and medication consumption in Cohort 1. Suppl Tab 2 Multivariable logistic regression for hospitalization status according to ethnicity and medication consumption in Cohort 2. Figure supplements Forest plot showing association between drug use and hospitalization risk in each of the cohorts, divided by body mass index (BMI) category.

https://cdn.elifesciences.org/articles/68165/elife-68165-supp1-v2.xlsx
Transparent reporting form
https://cdn.elifesciences.org/articles/68165/elife-68165-transrepform-v2.docx

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