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Metformin for COVID-19: real-time meta analysis of 40 studies
Covid Analysis, July 6, 2022, DRAFT
https://c19early.com/mfmeta.html
0 0.5 1 1.5+ All studies 29% 40 145,044 Improvement, Studies, Patients Relative Risk Mortality 36% 32 100,770 Ventilation 37% 5 1,371 ICU admission 10% 3 29,616 Hospitalization 20% 8 24,275 Progression 28% 5 3,719 Recovery 38% 2 4,008 Cases 4% 5 27,298 Viral clearance 1% 1 418 RCTs 27% 1 418 Peer-reviewed 29% 38 122,845 Prophylaxis 26% 37 117,930 Early 57% 2 26,926 Late 97% 1 188 Metformin for COVID-19 c19early.com/mf Jul 2022 Favorsmetformin Favorscontrol after exclusions
Statistically significant improvements are seen for mortality, ventilation, and hospitalization. 24 studies from 23 independent teams in 8 different countries show statistically significant improvements in isolation (21 for the most serious outcome).
Meta analysis using the most serious outcome reported shows 29% [23‑35%] improvement. Results are similar for Randomized Controlled Trials, similar after exclusions, and similar for peer-reviewed studies. Clinical outcomes suggest benefit while viral and case outcomes do not, consistent with an intervention that aids recovery but is not antiviral.
Results are robust — in exclusion sensitivity analysis 28 of 40 studies must be excluded to avoid finding statistically significant efficacy in pooled analysis.
0 0.5 1 1.5+ All studies 29% 40 145,044 Improvement, Studies, Patients Relative Risk Mortality 36% 32 100,770 Ventilation 37% 5 1,371 ICU admission 10% 3 29,616 Hospitalization 20% 8 24,275 Progression 28% 5 3,719 Recovery 38% 2 4,008 Cases 4% 5 27,298 Viral clearance 1% 1 418 RCTs 27% 1 418 Peer-reviewed 29% 38 122,845 Prophylaxis 26% 37 117,930 Early 57% 2 26,926 Late 97% 1 188 Metformin for COVID-19 c19early.com/mf Jul 2022 Favorsmetformin Favorscontrol after exclusions
Most studies analyze existing use with diabetic patients. Many results are subject to confounding by indication — metformin is typically used early in the progression of type 2 diabetes. Prophylaxis results typically include continuing use after infection and hospitalization, and greater benefit is seen for more serious outcomes. The beneficial effect of metformin may be more related to later stages of COVID-19. The TOGETHER RCT shows 27% lower mortality. While not statistically significant, p = 0.53, this is consistent with the mortality results from all studies, 36% [28‑43%].
While many treatments have some level of efficacy, they do not replace vaccines and other measures to avoid infection. None of the metformin studies show zero events in the treatment arm. Multiple treatments are typically used in combination, and other treatments are more effective.
No treatment, vaccine, or intervention is 100% available and effective for all variants. All practical, effective, and safe means should be used. Denying the efficacy of treatments increases mortality, morbidity, collateral damage, and endemic risk.
All data to reproduce this paper and sources are in the appendix. Other meta analyses for metformin can be found in [Hariyanto, Kow, Lukito, Yang], showing significant improvements for mortality and progression.
Highlights
Metformin reduces risk for COVID-19 with very high confidence for mortality, hospitalization, and in pooled analysis, high confidence for ventilation, low confidence for ICU admission, and very low confidence for recovery.
We show traditional outcome specific analyses and combined evidence from all studies, incorporating treatment delay, a primary confounding factor in COVID-19 studies.
Real-time updates and corrections, transparent analysis with all results in the same format, consistent protocol for 42 treatments.
A
0 0.25 0.5 0.75 1 1.25 1.5 1.75 2+ Reis (DB RCT) 27% 0.73 [0.28-1.94] death 7/215 9/203 Improvement, RR [CI] Treatment Control Hunt 67% 0.33 [0.25-0.43] death 73/3,956 1,539/22,552 Tau​2 = 0.19, I​2 = 59.6%, p = 0.022 Early treatment 57% 0.43 [0.21-0.89] 80/4,171 1,548/22,755 57% improvement Tamura 97% 0.03 [0.00-0.58] death 115 (n) 73 (n) Improvement, RR [CI] Treatment Control Tau​2 = 0.00, I​2 = 0.0%, p = 0.019 Late treatment 97% 0.03 [0.00-0.58] 0/115 0/73 97% improvement Luo 75% 0.25 [0.07-0.84] death 3/104 22/179 Improvement, RR [CI] Treatment Control Wang 58% 0.42 [0.01-1.98] death 1/9 13/49 Chen 33% 0.67 [0.20-1.78] death 4/43 15/77 Kim 64% 0.36 [0.10-1.23] death 113 (n) 122 (n) Li 78% 0.22 [0.09-0.54] death 2/37 21/94 Goodall 3% 0.97 [0.75-1.25] death 74/210 280/771 Gao -225% 3.25 [1.03-7.41] progression 16/56 4/54 Pérez-Belm.. (PSM) -10% 1.10 [0.84-1.40] death 79/249 79/249 Bramante 7% 0.93 [0.81-1.06] death 394/2,333 791/3,923 Lalau (PSM) 22% 0.78 [0.55-1.10] death 671 (n) 419 (n) Huh -1% 1.01 [0.75-1.37] progression 104/272 774/2,533 Crouse 61% 0.39 [0.16-0.87] death 8/76 34/144 Lally 52% 0.48 [0.28-0.84] death 16/127 144/648 Oh -26% 1.26 [0.81-1.95] death 5,946 (n) 5,946 (n) Wargny 28% 0.72 [0.53-0.95] death 247/1,553 330/1,241 Holt -27% 1.27 [0.72-2.22] cases 12/429 434/14,798 Khunti 23% 0.77 [0.73-0.81] death population-based cohort Jiang (PSM) 46% 0.54 [0.13-2.26] death 3/74 10/74 Ghany 66% 0.34 [0.19-0.59] death 392 (n) 747 (n) Alamgir 27% 0.73 [0.63-0.84] death 11,062 (n) 11,062 (n) Ravindra 30% 0.70 [0.28-1.56] death 5/53 57/313 Blanc 79% 0.21 [0.03-1.46] death 1/14 25/75 Boye 10% 0.90 [0.86-0.94] hosp. 2,067/4,250 3,196/5,281 Cheng (PSM) -65% 1.65 [0.71-3.86] death 678 (n) 535 (n) Wang 12% 0.88 [0.81-0.97] ICU 6,504 (n) 10,000 (n) Ando 39% 0.61 [0.38-0.99] hosp. Wander 15% 0.85 [0.80-0.90] death Saygili (PSM) 42% 0.58 [0.37-0.92] death 120 (n) 120 (n) Ong 47% 0.53 [0.31-0.87] death 33/186 57/169 Bliden 60% 0.40 [0.12-1.37] death 3/34 9/41 Al-Salameh 55% 0.45 [0.17-0.94] death/ICU 9/47 22/50 Wallace (PSW) 72% 0.28 [0.21-0.37] death 103/1,203 1,536/6,970 Ojeda-Ferná.. (PSM) 16% 0.84 [0.79-0.89] death 1,476/6,556 1,787/6,556 Usman 60% 0.40 [0.12-1.37] death 3/34 9/41 Wong 51% 0.49 [0.43-0.57] death Wong (PSW) 59% 0.41 [0.22-0.80] death 786 (n) 428 (n) MacFadden 1% 0.99 [0.96-1.01] cases n/a n/a Tau​2 = 0.03, I​2 = 92.0%, p < 0.0001 Prophylaxis 26% 0.74 [0.68-0.80] 4,663/44,221 9,649/73,709 26% improvement All studies 29% 0.71 [0.65-0.77] 4,743/48,507 11,197/96,537 29% improvement 40 metformin COVID-19 studies c19early.com/mf Jul 2022 Tau​2 = 0.04, I​2 = 92.5%, p < 0.0001 Effect extraction pre-specified(most serious outcome, see appendix) Favors metformin Favors control
0 0.25 0.5 0.75 1 1.25 1.5 1.75 2+ Reis (DB RCT) 27% death Improvement Relative Risk [CI] Hunt 67% death Tau​2 = 0.19, I​2 = 59.6%, p = 0.022 Early treatment 57% 57% improvement Tamura 97% death Tau​2 = 0.00, I​2 = 0.0%, p = 0.019 Late treatment 97% 97% improvement Luo 75% death Wang 58% death Chen 33% death Kim 64% death Li 78% death Goodall 3% death Gao -225% progression Pérez-Belm.. (PSM) -10% death Bramante 7% death Lalau (PSM) 22% death Huh -1% progression Crouse 61% death Lally 52% death Oh -26% death Wargny 28% death Holt -27% case Khunti 23% death Jiang (PSM) 46% death Ghany 66% death Alamgir 27% death Ravindra 30% death Blanc 79% death Boye 10% hospitalization Cheng (PSM) -65% death Wang 12% ICU admission Ando 39% hospitalization Wander 15% death Saygili (PSM) 42% death Ong 47% death Bliden 60% death Al-Salameh 55% death/ICU Wallace (PSW) 72% death Ojeda-Ferná.. (PSM) 16% death Usman 60% death Wong 51% death Wong (PSW) 59% death MacFadden 1% case Tau​2 = 0.03, I​2 = 92.0%, p < 0.0001 Prophylaxis 26% 26% improvement All studies 29% 29% improvement 40 metformin COVID-19 studies c19early.com/mf Jul 2022 Tau​2 = 0.04, I​2 = 92.5%, p < 0.0001 Effect extraction pre-specifiedRotate device for details Favors metformin Favors control
Figure 1. A. Random effects meta-analysis. This plot shows pooled effects, discussion can be found in the heterogeneity section, and results for specific outcomes can be found in the individual outcome analyses. Effect extraction is pre-specified, using the most serious outcome reported. For details of effect extraction see the appendix. B. Scatter plot showing the distribution of effects reported in studies. C. History of all reported effects (chronological within treatment stages).
Introduction
We analyze all significant studies concerning the use of metformin for COVID-19. Search methods, inclusion criteria, effect extraction criteria (more serious outcomes have priority), all individual study data, PRISMA answers, and statistical methods are detailed in Appendix 1. We present random effects meta-analysis results for all studies, for studies within each treatment stage, for individual outcomes, for peer-reviewed studies, for Randomized Controlled Trials (RCTs), and after exclusions.
Figure 2 shows stages of possible treatment for COVID-19. Prophylaxis refers to regularly taking medication before becoming sick, in order to prevent or minimize infection. Early Treatment refers to treatment immediately or soon after symptoms appear, while Late Treatment refers to more delayed treatment.
Figure 2. Treatment stages.
Preclinical Research
An In Vitro study supports the efficacy of metformin [Parthasarathy].
Preclinical research is an important part of the development of treatments, however results may be very different in clinical trials. Preclinical results are not used in this paper.
Results
Figure 3 shows a visual overview of the results, with details in Table 1 and Table 2. Figure 4, 5, 6, 7, 8, 9, 10, 11, 12, and 13 show forest plots for a random effects meta-analysis of all studies with pooled effects, mortality results, ventilation, ICU admission, hospitalization, progression, recovery, cases, viral clearance, and peer reviewed studies.
0 0.5 1 1.5+ ALL STUDIES MORTALITY VENTILATION ICU ADMISSION HOSPITALIZATION PROGRESSION RECOVERY CASES VIRAL CLEARANCE RANDOMIZED CONTROLLED TRIALS PEER-REVIEWED After Exclusions ALL STUDIES All Prophylaxis Early Late Metformin for COVID-19 C19EARLY.COM/MF JUL 2022
Figure 3. Overview of results.
Treatment timeNumber of studies reporting positive effects Total number of studiesPercentage of studies reporting positive effects Random effects meta-analysis results
Early treatment 2 2 100% 57% improvement
RR 0.43 [0.21‑0.89]
p = 0.022
Late treatment 1 1 100% 97% improvement
RR 0.03 [0.00‑0.58]
p = 0.019
Prophylaxis 31 37 83.8% 26% improvement
RR 0.74 [0.68‑0.80]
p < 0.0001
All studies 34 40 85.0% 29% improvement
RR 0.71 [0.65‑0.77]
p < 0.0001
Table 1. Results by treatment stage.
Studies Early treatment Late treatment Prophylaxis PatientsAuthors
All studies 4057% [11‑79%]97% [42‑100%]26% [20‑32%] 145,044 541
With exclusions 3757% [11‑79%]97% [42‑100%]27% [20‑33%] 129,376 484
Peer-reviewed 3857% [11‑79%]97% [42‑100%]26% [19‑32%] 122,845 521
Randomized Controlled TrialsRCTs 127% [-94‑72%] 418 23
Table 2. Results by treatment stage for all studies and with different exclusions.
0 0.25 0.5 0.75 1 1.25 1.5 1.75 2+ Reis (DB RCT) 27% 0.73 [0.28-1.94] death 7/215 9/203 Improvement, RR [CI] Treatment Control Hunt 67% 0.33 [0.25-0.43] death 73/3,956 1,539/22,552 Tau​2 = 0.19, I​2 = 59.6%, p = 0.022 Early treatment 57% 0.43 [0.21-0.89] 80/4,171 1,548/22,755 57% improvement Tamura 97% 0.03 [0.00-0.58] death 115 (n) 73 (n) Improvement, RR [CI] Treatment Control Tau​2 = 0.00, I​2 = 0.0%, p = 0.019 Late treatment 97% 0.03 [0.00-0.58] 0/115 0/73 97% improvement Luo 75% 0.25 [0.07-0.84] death 3/104 22/179 Improvement, RR [CI] Treatment Control Wang 58% 0.42 [0.01-1.98] death 1/9 13/49 Chen 33% 0.67 [0.20-1.78] death 4/43 15/77 Kim 64% 0.36 [0.10-1.23] death 113 (n) 122 (n) Li 78% 0.22 [0.09-0.54] death 2/37 21/94 Goodall 3% 0.97 [0.75-1.25] death 74/210 280/771 Gao -225% 3.25 [1.03-7.41] progression 16/56 4/54 Pérez-Belm.. (PSM) -10% 1.10 [0.84-1.40] death 79/249 79/249 Bramante 7% 0.93 [0.81-1.06] death 394/2,333 791/3,923 Lalau (PSM) 22% 0.78 [0.55-1.10] death 671 (n) 419 (n) Huh -1% 1.01 [0.75-1.37] progression 104/272 774/2,533 Crouse 61% 0.39 [0.16-0.87] death 8/76 34/144 Lally 52% 0.48 [0.28-0.84] death 16/127 144/648 Oh -26% 1.26 [0.81-1.95] death 5,946 (n) 5,946 (n) Wargny 28% 0.72 [0.53-0.95] death 247/1,553 330/1,241 Holt -27% 1.27 [0.72-2.22] cases 12/429 434/14,798 Khunti 23% 0.77 [0.73-0.81] death population-based cohort Jiang (PSM) 46% 0.54 [0.13-2.26] death 3/74 10/74 Ghany 66% 0.34 [0.19-0.59] death 392 (n) 747 (n) Alamgir 27% 0.73 [0.63-0.84] death 11,062 (n) 11,062 (n) Ravindra 30% 0.70 [0.28-1.56] death 5/53 57/313 Blanc 79% 0.21 [0.03-1.46] death 1/14 25/75 Boye 10% 0.90 [0.86-0.94] hosp. 2,067/4,250 3,196/5,281 Cheng (PSM) -65% 1.65 [0.71-3.86] death 678 (n) 535 (n) Wang 12% 0.88 [0.81-0.97] ICU 6,504 (n) 10,000 (n) Ando 39% 0.61 [0.38-0.99] hosp. Wander 15% 0.85 [0.80-0.90] death Saygili (PSM) 42% 0.58 [0.37-0.92] death 120 (n) 120 (n) Ong 47% 0.53 [0.31-0.87] death 33/186 57/169 Bliden 60% 0.40 [0.12-1.37] death 3/34 9/41 Al-Salameh 55% 0.45 [0.17-0.94] death/ICU 9/47 22/50 Wallace (PSW) 72% 0.28 [0.21-0.37] death 103/1,203 1,536/6,970 Ojeda-Ferná.. (PSM) 16% 0.84 [0.79-0.89] death 1,476/6,556 1,787/6,556 Usman 60% 0.40 [0.12-1.37] death 3/34 9/41 Wong 51% 0.49 [0.43-0.57] death Wong (PSW) 59% 0.41 [0.22-0.80] death 786 (n) 428 (n) MacFadden 1% 0.99 [0.96-1.01] cases n/a n/a Tau​2 = 0.03, I​2 = 92.0%, p < 0.0001 Prophylaxis 26% 0.74 [0.68-0.80] 4,663/44,221 9,649/73,709 26% improvement All studies 29% 0.71 [0.65-0.77] 4,743/48,507 11,197/96,537 29% improvement 40 metformin COVID-19 studies c19early.com/mf Jul 2022 Tau​2 = 0.04, I​2 = 92.5%, p < 0.0001 Effect extraction pre-specified(most serious outcome, see appendix) Favors metformin Favors control
0 0.25 0.5 0.75 1 1.25 1.5 1.75 2+ Reis (DB RCT) 27% death Improvement Relative Risk [CI] Hunt 67% death Tau​2 = 0.19, I​2 = 59.6%, p = 0.022 Early treatment 57% 57% improvement Tamura 97% death Tau​2 = 0.00, I​2 = 0.0%, p = 0.019 Late treatment 97% 97% improvement Luo 75% death Wang 58% death Chen 33% death Kim 64% death Li 78% death Goodall 3% death Gao -225% progression Pérez-Belm.. (PSM) -10% death Bramante 7% death Lalau (PSM) 22% death Huh -1% progression Crouse 61% death Lally 52% death Oh -26% death Wargny 28% death Holt -27% case Khunti 23% death Jiang (PSM) 46% death Ghany 66% death Alamgir 27% death Ravindra 30% death Blanc 79% death Boye 10% hospitalization Cheng (PSM) -65% death Wang 12% ICU admission Ando 39% hospitalization Wander 15% death Saygili (PSM) 42% death Ong 47% death Bliden 60% death Al-Salameh 55% death/ICU Wallace (PSW) 72% death Ojeda-Ferná.. (PSM) 16% death Usman 60% death Wong 51% death Wong (PSW) 59% death MacFadden 1% case Tau​2 = 0.03, I​2 = 92.0%, p < 0.0001 Prophylaxis 26% 26% improvement All studies 29% 29% improvement 40 metformin COVID-19 studies c19early.com/mf Jul 2022 Tau​2 = 0.04, I​2 = 92.5%, p < 0.0001 Effect extraction pre-specifiedRotate device for details Favors metformin Favors control
Figure 4. Random effects meta-analysis for all studies with pooled effects. This plot shows pooled effects, discussion can be found in the heterogeneity section, and results for specific outcomes can be found in the individual outcome analyses. Effect extraction is pre-specified, using the most serious outcome reported. For details of effect extraction see the appendix.
0 0.25 0.5 0.75 1 1.25 1.5 1.75 2+ Reis (DB RCT) 27% 0.73 [0.28-1.94] 7/215 9/203 Improvement, RR [CI] Treatment Control Hunt 67% 0.33 [0.25-0.43] 73/3,956 1,539/22,552 Tau​2 = 0.19, I​2 = 59.6%, p = 0.022 Early treatment 57% 0.43 [0.21-0.89] 80/4,171 1,548/22,755 57% improvement Tamura 97% 0.03 [0.00-0.58] 115 (n) 73 (n) Improvement, RR [CI] Treatment Control Tau​2 = 0.00, I​2 = 0.0%, p = 0.019 Late treatment 97% 0.03 [0.00-0.58] 0/115 0/73 97% improvement Luo 75% 0.25 [0.07-0.84] 3/104 22/179 Improvement, RR [CI] Treatment Control Wang 58% 0.42 [0.01-1.98] 1/9 13/49 Chen 33% 0.67 [0.20-1.78] 4/43 15/77 Kim 64% 0.36 [0.10-1.23] 113 (n) 122 (n) Li 78% 0.22 [0.09-0.54] 2/37 21/94 Goodall 3% 0.97 [0.75-1.25] 74/210 280/771 Pérez-Belm.. (PSM) -10% 1.10 [0.84-1.40] 79/249 79/249 Bramante 7% 0.93 [0.81-1.06] 394/2,333 791/3,923 Lalau (PSM) 22% 0.78 [0.55-1.10] 671 (n) 419 (n) Crouse 61% 0.39 [0.16-0.87] 8/76 34/144 Lally 52% 0.48 [0.28-0.84] 16/127 144/648 Oh -26% 1.26 [0.81-1.95] 5,946 (n) 5,946 (n) Wargny 28% 0.72 [0.53-0.95] 247/1,553 330/1,241 Khunti 23% 0.77 [0.73-0.81] population-based cohort Jiang (PSM) 46% 0.54 [0.13-2.26] 3/74 10/74 Ghany 66% 0.34 [0.19-0.59] 392 (n) 747 (n) Alamgir 27% 0.73 [0.63-0.84] 11,062 (n) 11,062 (n) Ravindra 30% 0.70 [0.28-1.56] 5/53 57/313 Blanc 79% 0.21 [0.03-1.46] 1/14 25/75 Cheng (PSM) -65% 1.65 [0.71-3.86] 678 (n) 535 (n) Wander 15% 0.85 [0.80-0.90] Saygili (PSM) 42% 0.58 [0.37-0.92] 120 (n) 120 (n) Ong 47% 0.53 [0.31-0.87] 33/186 57/169 Bliden 60% 0.40 [0.12-1.37] 3/34 9/41 Wallace (PSW) 72% 0.28 [0.21-0.37] 103/1,203 1,536/6,970 Ojeda-Ferná.. (PSM) 16% 0.84 [0.79-0.89] 1,476/6,556 1,787/6,556 Usman 60% 0.40 [0.12-1.37] 3/34 9/41 Wong 51% 0.49 [0.43-0.57] Wong (PSW) 59% 0.41 [0.22-0.80] 786 (n) 428 (n) Tau​2 = 0.04, I​2 = 88.2%, p < 0.0001 Prophylaxis 33% 0.67 [0.60-0.75] 2,455/32,663 5,219/40,993 33% improvement All studies 36% 0.64 [0.57-0.72] 2,535/36,949 6,767/63,821 36% improvement 32 metformin COVID-19 mortality results c19early.com/mf Jul 2022 Tau​2 = 0.05, I​2 = 89.4%, p < 0.0001 Favors metformin Favors control
Figure 5. Random effects meta-analysis for mortality results.
0 0.25 0.5 0.75 1 1.25 1.5 1.75 2+ Li -27% 1.27 [0.12-13.6] 1/37 2/94 Improvement, RR [CI] Treatment Control Lalau (PSM) 7% 0.93 [0.64-1.35] 671 (n) 419 (n) Bliden 76% 0.24 [0.06-1.03] 2/34 10/41 Usman 76% 0.24 [0.06-1.03] 2/34 10/41 Wong 41% 0.59 [0.52-0.66] Tau​2 = 0.08, I​2 = 54.7%, p = 0.023 Prophylaxis 37% 0.63 [0.42-0.94] 5/776 22/595 37% improvement All studies 37% 0.63 [0.42-0.94] 5/776 22/595 37% improvement 5 metformin COVID-19 mechanical ventilation results c19early.com/mf Jul 2022 Tau​2 = 0.08, I​2 = 54.7%, p = 0.023 Favors metformin Favors control
Figure 6. Random effects meta-analysis for ventilation.
0 0.25 0.5 0.75 1 1.25 1.5 1.75 2+ Wang 12% 0.88 [0.81-0.97] 6,504 (n) 10,000 (n) Improvement, RR [CI] Treatment Control Wander 2% 0.98 [0.92-1.06] Ojeda-Ferná.. (PSM) 22% 0.78 [0.64-0.95] 166/6,556 212/6,556 Tau​2 = 0.01, I​2 = 70.4%, p = 0.065 Prophylaxis 10% 0.90 [0.80-1.01] 166/13,060 212/16,556 10% improvement All studies 10% 0.90 [0.80-1.01] 166/13,060 212/16,556 10% improvement 3 metformin COVID-19 ICU results c19early.com/mf Jul 2022 Tau​2 = 0.01, I​2 = 70.4%, p = 0.065 Favors metformin Favors control
Figure 7. Random effects meta-analysis for ICU admission.
0 0.25 0.5 0.75 1 1.25 1.5 1.75 2+ Reis (DB RCT) 6% 0.94 [0.55-1.61] hosp. 24/215 24/203 Improvement, RR [CI] Treatment Control Tau​2 = 0.00, I​2 = 0.0%, p = 0.84 Early treatment 6% 0.94 [0.55-1.61] 24/215 24/203 6% improvement Ghany 29% 0.71 [0.52-0.86] hosp. 392 (n) 747 (n) Improvement, RR [CI] Treatment Control Boye 10% 0.90 [0.86-0.94] hosp. 2,067/4,250 3,196/5,281