Table 1 Characteristics of included reviews

Abuzaid (2018) [17]

Severe aortic stenosis

Dual anti-platelet therapy (DAPT)

Single anti-platelet therapy (SAPT)

30-day all-cause mortality

3

7

RR 1.2 (0.5–2.89)

RR 1.19 (0.74–1.91)

Abuzaid (2018) [17]

Severe aortic stenosis

DAPT

SAPT

Longest reported all-cause mortality

3

7

RR 1.14 (0.54–2.42)

RR 1.06 (0.52–2.18)

Abuzaid (2018) [17]

Severe aortic stenosis

DAPT

SAPT

Major bleeding

3

7

RR 1.74 (0.52–5.82)

RR 2.23 (1.36–3.65)

Agarwal (2019) [18]

Acute coronary syndrome (ACS), coronary artery disease (CAD)

Dual therapy

Triple therapy

Major bleeding

3

3

RR 0.53 (0.38–0.76)

RR 0.88 (0.46–1.67)

Agarwal (2018) [19]

CAD

DAPT

Aspirin

Primary outcome: mid- to long-term (> 30 days) composite of myocardial infarction (MI), stroke, or death

8

4

RR 0.43 (0.17–1.11)

RR 0.85 (0.72–1.01)

An (2019) [20]

Severe aortic stenosis

Antiplatelet

Anticoagulation

Mortality

2

5

RR 0.82 (0.33–2.03)

RR 0.47 (0.18–1.22)

An (2019) [20]

Severe aortic stenosis

Antiplatelet

Anticoagulation

Stroke/transient ischemic attack (TIA)

2

5

RR 0.9 (0.35–2.33)

RR 0.57 (0.31–1.03)

An (2019) [20]

Severe aortic stenosis

Antiplatelet

Anticoagulation

Thromboembolic events

2

5

RR 1.13 (0.51–2.49)

RR 0.71 (0.38–1.32)

An (2019) [20]

Severe aortic stenosis

Antiplatelet

Anticoagulation

Bleeding

2

5

RR 0.34 (0.11–1.04)

RR 0.34 (0.2–0.58)

Chien (2020)* [21]

Multi-drug resistant gram-negative bacteria (MDR-GNB) infections

Colistin

Other antibiotics

Colistin-associated acute kidney injury (CA-AKI)

1

19

OR 2.75 (0.43–17.49)

Not reported

Chien (2020) [21]

MDR-GNB infections

Colistin monotherapy

Colistin combination therapy

Acute kidney injury (AKI)

3

6

OR 1.77 (1.17–2.66)

OR 1.15 (0.76–1.76)

Chopra (2012)* [22]

Pneumonia

Statin therapy

No statin therapy

Unadjusted all-cause mortality following an episode of pneumonia

1

9

OR 0.84 (0.32–2.18)

Not reported

Chopra (2012) [22]

Pneumonia

Statin therapy

No statin therapy

Adjusted all-cause mortality following an episode of pneumonia

1

11

OR 0.84 (0.32–2.18)

OR 0.66 (0.55–0.79)

Desai (2016) [23]

Ankylosing spondylitis, inflammatory bowel diseases, juvenile idiopathic arthritis, plaque psoriasis, psoriatic arthritis, and rheumatoid arthritis

Adalimumab

Etanercept

Discontinuation due to adverse events

1

3

RR 0.83 (0.39–1.78)

Adjusted HR 1.67 (1.26–2.22)

Desai (2016) [23]

Ankylosing spondylitis, inflammatory bowel diseases, juvenile idiopathic arthritis, plaque psoriasis, psoriatic arthritis, rheumatoid arthritis

Adalimumab

Infliximab

Discontinuation due to adverse events

1

5

RR 6.17 (0.78–48.71)

Adjusted HR 0.57 (0.46–0.7)

Gandhi (2015) [24]

Aortic stenosis

DAPT

Mono-antiplatelet therapy (MAPT).

Combined end point of 30-day major stroke, spontaneous MI, all-cause mortality, and combined lethal and major bleeding

2

2

OR 0.98 (0.46–2.11)

OR 3.02 (1.91–4.76)

Ge (2018) [25]

Atrial fibrillation

Novel oral anticoagulants (NOACs)

Vitamin K antagonists (VKAs)

Major bleeding events (Fixed effects model)

4

25

OR 0.3 (0.14–0.62)

OR 0.68 (0.48–0.95)

Ge (2018) [25]

Atrial fibrillation

NOACs

VKAs

Thromboembolic events (Fixed effects model)

4

25

OR 0.14 (0.01–1.3)

OR 0.91 (0.49–1.67)

Heffernan (2020) [26]

Serious infections

β-lactam/aminoglycoside combination therapy

β-lactam monotherapy

All-cause mortality

2

4

OR 3.18 (0.79–12.73)

OR 0.79 (0.64–0.99)

Ho (2013) [27]

Kidney disease (kidney transplant)

Once daily tacrolimus

Twice daily tacrolimus

Biopsy-proven acute rejection (RCT: at 6 months; Observational: mean follow-up ranges from 3 months to 672 months)

4

5

RR 1.18 (0.82–1.68)

RR 0.83 (0.39–1.78)

Ho (2013) [27]

Kidney disease (kidney transplant)

Once daily tacrolimus

Twice daily tacrolimus

Biopsy-proven acute rejection (RCT: at 12 months

Observational: mean follow-up ranges from 3 months to 672 months)

2

5

RR 1.24 (0.93–1.65)

RR 0.83 (0.39–1.78)

Ho (2013) [27]

Kidney disease (kidney transplant)

RCT: twice daily tacrolimus

Observational: once daily tacrolimus

RCT: once daily tacrolimus

Observational: twice daily tacrolimus

Patient survival (RCT: at 6 months

Observational: mean follow-up ranges from 3.5 months to 12 months)

2

2

RR 1.03 (1–1.06)

RR 1.02 (0.94–1.1)

Ho (2013) [27]

Kidney disease (kidney transplant)

RCT: twice daily tacrolimus

Observational: once daily tacrolimus

RCT: once daily tacrolimus

Observational: twice daily tacrolimus

Patient survival (RCT: at 12 months

Observational: mean follow-up ranges from 3.5 months to 12 months)

3

2

RR 0.99 (0.97–1.02)

RR 1.02 (0.94–1.1)

Khan (2019) [28]

CAD

Proton pump inhibitor (PPI)

No PPI

All-cause mortality

3

24

RR 1.35 (0.56–3.23)

RR 1.25 (1.11–1.41)

Kirson (2013)* [29]

Schizophrenia

Depot antipsychotics

Oral antipsychotics

Varies across studies: hospitalization, relapse, discontinuation

5

8

RR 0.89 (0.64–1.22)

Not reported

Land (2017) [30]

Psychiatric illnesses

Clozapine

Control drugs (other antipsychotics)

Hospitalization

3

19

RR 0.62 (0.41–0.94)

RR 0.75 (0.69–0.81)

Li (2016) [31]

Diabetes

Dipeptidyl peptidase-4 (DPP-4) inhibitors

RCT: control

Observational: sulfonylurea (SU)

Heart failure

38

1

OR 0.97 (0.61–1.56)

Unadjusted OR 0.88 (0.22–3.48)

Li (2016) [31]

Diabetes

DPP-4 inhibitors

RCT: control

Observational: SU

Heart failure

38

1

OR 0.97 (0.61–1.56)

Adjusted HR 1.10 (1.04–1.17)

Li (2016) [31]

Diabetes

RCT: DPP-4 inhibitors

Observational: sitagliptin

RCT: control

Observational: SU

Heart failure

38

1

OR 0.97 (0.61–1.56)

Unadjusted OR 0.39 (0.02–6.26)

Li (2016) [31]

Diabetes

RCT: DPP-4 inhibitors

Observational: sitagliptin

RCT: control

Observational: no sitagliptin use

Heart failure

38

1

OR 0.97 (0.61–1.56)

Adjusted OR 0.75 (0.38–1.46)

Li (2016) [31]

Diabetes

DPP-4 inhibitors

RCT: control

Observational: active control

Hospital admission for heart failure

5

6

OR 1.13 (1.00–1.26)

Adjusted OR 0.85 (0.74–0.97)

Li (2016) [31]

Diabetes

DPP-4 inhibitors

RCT: control

Observational: SU

Hospital admission for heart failure

5

3

OR 1.13 (1.00–1.26)

Adjusted HR 0.84 (0.74–0.96)

Li (2016) [31]

Diabetes

DPP-4 inhibitors

RCT: control

Observational: pioglitazone

Hospital admission for heart failure

5

2

OR 1.13 (1.00–1.26)

Adjusted HR 0.67 (0.57–0.78)

Li (2016) [31]

Diabetes

DPP-4 inhibitors

RCT: control

Observational: other oral antidiabetics

Hospital admission for heart failure

5

1

OR 1.13 (1.00–1.26)

Adjusted OR 0.88 (0.63–1.22)

Li (2016) [31]

Diabetes

DPP-4 inhibitors

Control

Hospital admission for heart failure

5

1

OR 1.13 (1.00–1.26)

Adjusted HR 0.58 (0.38–0.88)

Li (2016) [31]

Diabetes

RCT: DPP-4 inhibitors

Observational: sitagliptin

RCT: control

Observational: no sitagliptin use

Hospital admission for heart failure

5

2

OR 1.13 (1.00–1.26)

Adjusted OR 1.41 (0.95–2.09)

Li (2016) [31]

Diabetes

RCT: DPP-4 inhibitors

Observational: sitagliptin

RCT: control

Observational: no sitagliptin use

Hospital admission for heart failure

5

1

OR 1.13 (1.00–1.26)

Adjusted HR 1.21 (1.04–1.42)

Li (2016) [31]

Diabetes

RCT: DPP-4 inhibitors

Observational: sitagliptin

RCT: control

Observational: no sitagliptin use

Hospital admission for heart failure

5

1

OR 1.13 (1.00–1.26)

Adjusted OR 1.84 (1.16–2.92)

Melloni (2015) [32]

Unstable angina/non–ST-segment–elevation myocardial infarction (UA/NSTEMI)

RCT: omeprazole

Observational: any PPI

RCT: placebo

Observational: no PPI

Composite ischemic endpoint at ≈ 1 year

1

20

HR 0.99 (0.68–1.44)

Adjusted HR 1.35 (1.18–1.54)

Melloni (2015) [32]

UA/NSTEMI

RCT: omeprazole

Observational: any PPI

RCT: placebo

Observational: no PPI

Nonfatal MI at ≈ 1 year

1

10

HR 0.92 (0.44–1.9)

HR 1.331 (1.146–1.547)

Miles (2019) [33]

Heart failure

Furosemide

Torsemide

All-cause mortality

5

3

OR 1.12 (0.7–1.8)

OR 0.97 (0.44–2.13)

Miles (2019) [33]

Heart failure

Furosemide

Torsemide

Heart failure readmissions

4

1

OR 2.04 (1.16–3.60)

OR 2.91 (0.78–10.91)

Miles (2019) [33]

Heart failure

Furosemide

Torsemide

New York Heart Association class improvement

7

2

OR 0.91 (0.61–1.35)

OR 0.65 (0.50–0.85)

Mongkhon (2019) [34]

Atrial fibrillation

OAC

Non-OAC

Risk of dementia

1

4

RR 1.31 (0.79–2.18)

RR 0.75 (0.67–0.83)

Mongkhon (2019) [34]

Atrial fibrillation

VKA

Non-VKA

Risk of dementia

1

4

RR 1.31 (0.79–2.18)

RR 0.71 (0.68–0.74)

Raheja (2018) [35]

Aortic stenosis

DAPT

SAPT

All-cause mortality

3

2

RR 1.07 (0.48–2.41)

RR 1.34 (0.51–3.48)

Raheja (2018) [35]

Aortic stenosis

DAPT

SAPT

Stroke or TIA

3

2

RR 0.93 (0.28–3.06)

RR 1.25 (0.32–4.92)

Raheja (2018) [35]

Aortic stenosis

DAPT

SAPT

MI

3

2

RR 3.62 (0.60–21.76)

RR 1.18 (0.14–9.98)

Raheja (2018) [35]

Aortic stenosis

DAPT

SAPT

Major/life-threatening bleeding

3

3

RR 1.75 (0.88–3.50)

RR 3.24 (1.82–5.75)

Ramjan (2014) [36]

HIV

Fixed-dose combination (FDC) antiretroviral therapy (ART)

Separate tablet regimens

Virological suppression

4

2

RR 1.04 (0.98–1.10)

RR 1.07 (0.97–1.18)

Ramjan (2014) [36]

HIV

FDC ART

Separate tablet regimens

Adherence to ART

5

2

RR 1.1 (0.98–1.22)

RR 1.17 (1.07–1.28)

Shi (2014) [37]

Liver cancer

Statins

Placebo/non-use

Liver cancer

1

11

RR 1.06 (0.66–1.71)

RR 0.57 (0.50–0.64)

Teo (2014) [38]

Acute infections

Prolonged infusion, which was defined as administration of either extended infusion or continuous infusion of beta-lactam antibiotics

Identical beta-lactams that were administered as intermittent boluses (20–60 min infusion) according to the manufacturer’s package insert

All-cause in-hospital mortality

10

9

RR 0.83 (0.57–1.21)

RR 0.57 (0.43–0.76)

Teo (2014) [38]

Acute infections

Prolonged infusion, which was defined as administration of either extended infusion or continuous infusion of beta-lactam antibiotics.

Identical beta-lactams that were administered as intermittent boluses (20–60 min infusion) according to the manufacturer’s package insert

Clinical success (cure or improvement)

14

5

RR 1.05 (0.99–1.12)

RR 1.34 (1.02–1.76)

Vinceti (2018) [39]

Cancer

Highest selenium exposure

Lowest selenium exposure

Total (any) cancer incidence

3

7

RR 1.01 (0.93–1.10)

OR 0.72 (0.55–0.93)

Vinceti (2018) [39]

Cancer

Highest selenium exposure

Lowest selenium exposure

Cancer mortality

1

7

RR 1.02 (0.80–1.30)

OR 0.76 (0.59–0.97)

Vinceti (2018) [39]

Colorectal cancer

Highest selenium exposure

Lowest selenium exposure

Colorectal cancer risk

2

1

RR 0.99 (0.69–1.43)

OR 0.80 (0.68–0.94)

Vinceti (2018) [39]

Lung cancer

Highest selenium exposure

Lowest selenium exposure

Lung cancer risk

2

5

RR 1.16 (0.89–1.50)

OR 0.74 (0.43–1.28)

Vinceti (2018) [39]

Breast cancer

Highest selenium exposure

Lowest selenium exposure

Breast cancer risk

1

8

RR 2.04 (0.44–9.55)

OR 1.09 (0.87–1.37)

Vinceti (2018) [39]

Bladder cancer

Highest selenium exposure

Lowest selenium exposure

Bladder cancer risk

2

2

RR 1.07 (0.76–1.52)

OR 0.65 (0.46–0.92)

Vinceti (2018) [39]

Prostate cancer

Highest selenium exposure

Lowest selenium exposure

Prostate cancer risk

4

21

RR 1.01 (0.90–1.14)

OR 0.84 (0.75–0.95)

Wang (2019) [40]

Pneumonia

PPI

No PPI

Pneumonia

10

48

OR 1.13 (0.71–1.78)

OR 1.45 (1.32–1.59)

Wat (2019) [41]

Traumatic brain injury (TBI)

Antiepileptic drugs

Placebo/no treatment

Early seizures after TBI

3

6

RR 0.58 (0.20–1.72)

RR 0.42 (0.29–0.62)

Wong (2017)* [42]

Coronary heart disease/CAD

Macrolides

Placebo/no treatment

Short-term primary outcome (defined as cardiac mortality, cardiovascular mortality, sudden death, cardiac arrest, all-cause mortality, or composite outcomes including death and/or other cardiovascular events or procedures)

5

15

RR 0.99 (0.74–1.34)

Not reported

Wong (2017) [42]

Coronary heart disease/CAD

Macrolides

Placebo/no treatment

Long term primary outcome (defined as cardiac mortality, cardiovascular mortality, sudden death, cardiac arrest, all-cause mortality, or composite outcomes including death and/or other cardiovascular events or procedures)

14

8

RR 1.03 (0.96–1.10)

RR 1.05 (0.91–1.22)

Yang (2019)* [43]

Cancer

Epoetin alfa biosimilar drugs

Epoetin alfa drugs

Mean of hemoglobin increase

1

4

WMD -0.02 (− 0.38–0.34)

WMD 0.07 (− 0.12–0.25)

Yang (2019) [43]

Cancer

Epoetin alfa biosimilar drugs

Epoetin alfa drugs

Hemoglobin response

1

1

RR 1.09 (0.86–1.38)

RR 1.18 (0.87–1.60)

Yang (2019) [43]

Breast cancer

Granulocyte colony-stimulating factor (G-CSF) biosimilar drugs

G-CSF drugs

Febrile neutropenia in cycle 1

5

3

RR 1.14 (0.80–1.63)

RR 1.36 (0.84–2.23)

Yang (2019) [43]

NHL

G-CSF biosimilar drugs

G-CSF drugs

Febrile neutropenia in cycle 1

1

1

RR 0.54 (0.20–1.46)

RR 0.87 (0.20–3.85)

Yang (2019) [43]

Cancer

G-CSF biosimilar drugs (filgrastim biosimilars)

G-CSF drugs

Bone pain

4

4

RR 0.90 (0.78–1.05)

RR 0.86 (0.59–1.24)

Yu (2018) [44]

Non-cardiac vascular disease

Statins

Placebo/no statin treatment

All-cause mortality

3

6

OR 0.62 (0.41–0.92)

OR 0.65 (0.48–0.88)

Yu (2018) [44]

Non-cardiac vascular disease

Statins

Placebo/no statin treatment

Primary patency

1

10

OR 0.39 (0.09–1.65)

OR 0.77 (0.59–0.99)

Yu (2018) [44]

Non-cardiac vascular disease

Statins

Placebo/no statin treatment

Amputation

1

10

OR 0.47 (0.07–2.94)

OR 0.64 (0.50–0.83)

Yu (2018) [44]

Non-cardiac vascular disease

Statins

Placebo/no statin treatment

Cardiovascular events

3

2

OR 0.55 (0.36–0.83)

OR 0.87 (0.16–4.60)

Zhang (2019) [45]

Atrial fibrillation

NOAC

Non-NOAC therapy

Renal impairment

11

3

HR 0.82 (0.71–0.93)

HR 0.64 (0.58–0.69)

Zhao (2018) [46]

CAD

DAPT

SAPT

Any bleeding events

5

8

RR 1.25 (0.98–1.59)

RR 0.87 (0.76–1.01)

Zhao (2018) [46]

CAD

DAPT

SAPT

Minor bleeding events

4

3

RR 1.15 (0.73–1.81)

RR 0.84 (0.37–1.93)

Zhao (2018) [46]

CAD

DAPT

SAPT

Major bleeding events

5

6

RR 1.28 (0.95–1.71)

RR 0.99 (0.66–1.51)

Zhao (2018) [46]

CAD

DAPT

SAPT

Major bleeding events during hospitalization (random effects model)

3

3

RR 1.27 (0.91–1.78)

RR 0.50 (0.12–2.09)