Study reference

Study characteristics

Patient characteristics ²

Intervention (I)

Comparison / control (C) ³

Follow-up

Outcome measures and effect size ⁴

Comments

Baratz et al. (2015)

Type of study:
Retrospective clinical study

Setting:

Hospital-based

Country:
United States of America (USA)

Source of funding:
Not mentioned (only mentioned that the authors or a member of his or her immediate family, has no funding or commercial associations that might pose a conflict of interest in connection with the submitted article)

Inclusion criteria for intervention group:

In this study all patients undergoing primary or revision THA or TKA over a 2-year period at a single institution were included.

Exclusion criteria for intervention group:

Patients were excluded if they had a history of infection at the operative site

Inclusion/exclusion criteria for control group:
Not given

N total at baseline:

Intervention: 3080

Control: 3434

Important prognostic factors²:

No baseline values were given

Groups comparable at baseline?

Not possible to assess

Describe intervention (treatment/procedure/test):

Two weeks before the intended surgical date, all patients were screened for nasal colonization with MSSA and MRSA. Microbiologic samples were obtained by trained nurses in the preoperative area using a nasal swab on the inside of the nares for 5 seconds in each naris. Samples were sent for rapid polymerase chain reaction (PCR) using GeneXpert1 XVI (Cepheid, Sunnyvale, CA, USA) for the detection of MRSA. Standard culture was used for the detection of MSSA.

Patients determined to be carriers of either MSSA or MRSA were provided treatment with intranasal 2% mupirocin ointment (Bactroban; GlaxoSmithKline, Middlesex, UK)

twice daily for 5 days and daily skin cleansing with 4% chlorhexidine soap (Dyna-Hex 4; Xttrium Laboratories, Chicago, IL, USA) for 5 days, including the day of surgery. Patients who were colonized received a phone call from a

preoperative nurse and were provided with instructions on the treatment protocol and literature supporting the use of both products. Patients colonized with MRSA at the initial preoperative visit were rescreened on the day of surgery using the identical screening protocol for MRSA. The results of the day-of-surgery rapid PCR were made available before the start of the procedure. Standard perioperative antibiotic prophylaxis was consisted of an intraoperative dose of a first generation cephalosporin (cefazolin) followed by two additional doses postoperatively at 8-hour intervals. Patients with a ß-lactam allergy, patients were treated with an intraoperative dose of vancomycin and one additional dose 12 hours postoperatively. Patients

colonized with MRSA at either the 2-week preoperative screening visit or on the day-of-surgery screening received

a single intraoperative dose of vancomycin in addition to the standard protocol of cefazolin. Patients who remained colonized with MRSA on the day of surgery were placed on isolation precautions during their hospitalization. Patients were monitored prospectively for SSI by a hospital-employed nurse responsible for quality control and infection prevention.

Describe control (treatment/procedure/test):
A patient group from a 2-year period before the implementation of the screening and decolonisation protocol (January 2009 to December 2010).

It is not written what the treatment was of patients in the control group.

Length of follow-up:

Not given (SSI was defined as a hospital-acquired infection related to a surgical procedure as any infection diagnosed within 1 year of the procedure)

Loss-to-follow-up:

Not given

Incomplete outcome data:

Unclear

Outcome measures and effect size (include 95%CI and p-value if available):

2009 to 2010
Primary cases: 2513
Primary infections: 19 (1%)
Revision cases: 567
Revision infections: 14 (3%)

All cases: 3080
All infections: 33 (1%)

2012 to 2013
Primary cases: 2903
Primary infections: 17 (1%)
Revision cases: 531
Revision infections: 10 (2%)
All cases: 3434

All infections: 27 (1%)

Relative risk (95% CI)
Primary cases: 0.77 (0.40 – 1.49)
p-value = 0.51
Revision cases: 0.76 (0.34 – 1.7)
p-value = 0.65
All cases: 0.74 (0.44 - 1.22)
p-value = 0.28

No baseline values were given.

It is not written if patients in the historical control group were treated with antibiotic prophylaxis.

Incomplete outcome data is possible, because how outcome data was measured is not given.

Sporer et al. (2016)

Type of study:
Observational study

Setting:

Hospital-based

Country:
United States of America (USA)

Source of funding:
Not mentioned (only mentioned that one or more of the authors of this paper have disclosed potential or pertinent conflict of interest, which may include receipt of payment, either direct or indirect, institutional support, or association with an entity in the biomedical field which may be perceived to have potential conflict of interest with this work)

Inclusion criteria intervention group:

All patients who underwent primary THA or TKA between 2009 and 2014 were included in this study.

Exclusion criteria intervention group:

Not mentioned

Inclusion / exclusion criteria control group:
Patients undergoing similar elective joint arthroplasty between January 1, 2008 and December 31, 2008 served as a control population.
N total at baseline:

Intervention: 9825

Control: 1443

Important prognostic factors²:

Age (N(%)):
2008
<50 = 119 (8.3)
50 -59 = 376 (26.1)
60 to 69 = 452 (31.4)
70 to 79 = 360 (25.0)

≥ 80 = 133 (9.2)

2009
<50 = 114 (7.5)
50 -59 = 370 (24.3)
60 to 69 = 521 (34.2)
70 to 79 = 354 (23.3)

≥ 80 = 163 (10.7)

2010
<50 = 118 (7.1)
50 -59 = 446 (26.7)
60 to 69 = 568 (34.1)
70 to 79 = 405 (24.3)

≥ 80 = 130 (7.8)

2011
<50 = 94 (6.1)
50 -59 = 374 (24.4)
60 to 69 = 546 (35.6)
70 to 79 = 371 (24.4)

≥ 80 = 145 (9.5)

2012
<50 = 104 (6.1)
50 -59 = 397 (23.3)
60 to 69 = 622 (36.6)
70 to 79 = 416 (24.4)

≥80 = 163 (9.6)

2013
<50 = 86 (5.0)
50 -59 = 405 (23.6)
60 to 69 = 662 (38.6)
70 to 79 = 419 (24.4)

≥80 = 145 (8.4)

2014
 <50 = 101 (6.1)
50 -59 = 369 (22.3)
60 to 69 = 642 (38.8)
70 to 79 = 431 (26.1)

 80 = 110 (6.7)

Sex (male (N(%))
2008 = 593 (41.2)
2009 = 616 (40.5)

2010 = 673 (40.4)
2011 = 606 (39.6)
2012 = 702 (41.3)
2013 = 691 (40.2)
2014 = 684 (41.4)

Length of stay (days) (N (%))
2008
<3 days = 393 (27.3)
3 to 4 days = 930 (64.6)
>5 days = 117 (8.1)

2009
<3 days = 395 (26.0)
3 to 4 days = 1024 (67.3)
>5 days =103 (6.8)

2010
<3 days = 50.8 (30.5)
3 to 4 days = 1076 (64.5)
>5 days = 83 (5.0)

2011
<3 days = 386 (25.2)
3 to 4 days = 1072 (70.1)
>5 days = 72 (4.7)

2012
<3 days = 477 (28.0)
3 to 4 days = 1150 (67.6)
>5 days = 75 (4.4)

2013
<3 days = 526 (30.6)
3 to 4 days = 1123 (65.4)
>5 days = 68 (4.0)

2014
<3 days = 583 (35.3)
3 to 4 days = 994 (60.1)
>5 days = 76 (4.6)

Total
<3 days = 3268 (29.1)
3 to 4 days = 7369 (65.6)
>5 days = 594 (5.3)

Groups comparable at baseline?

Not comparable in age and length of stay

Describe intervention (treatment/procedure/test):

The hospital was started with screening for nasal colonization of MSSA and MRSA before elective surgical procedure in 2009. All surgical patients were instructed to obtain a nasal swab a minimum of 14 days before the planned surgical date. Standard microbiologic culture methods were used to identify MSSA and MRSA strains. Patients who tested positive for Staphylococcus aureus were notified of their results and were instructed to begin 2% mupirocin ointment (Bactroban; GlaxoSMithKline, Middlesex, United Kingdom) applied intranasally along with 2% chlorhexidine gluconate (CHG) showers (HiBiClens is 4%, CHG cloths are 2%; HiBiClens; Monlnlycke Health Care, Norcross, Georgia) 5 days before admission to the hospital. Patients were instructed to apply a pea-sized amount of ointment into each nostril twice daily, morning and evening, along with compressing the nares several times to distribute the ointment. Patients who tested positive for MRSA were treated with vancomycin within 2 hours before surgery. All other Staphylococcus aureus – positive patients were treated with cefazolin within an hour of surgery. Antibiotic prophylaxis was then discontinued with 24 hours after the surgical procedure. In addition, patients who tested positive for MRSA colonization were placed on contact precautions that included the use of barrier gowns and gloves during patient contact. Patients identified as positive for either MSSA or MRSA less than 5 days before admission began CHG showers as soon as possible and continued them until admission. Intranasal decolonisation of these patients identified less than 5 days before surgery continued mupirocin until completion of 10 doses. Patients of unknown colonization status were screened on the day of admission. Mupirocin was administered immediately before surgery in this cohort of patients and was continued postoperatively until the screening results were negative either MSSA or MRSA or the patient completed the 10-dose decolonisation regime. All patients regardless of nasal colonization, were instructed to shower the night before surgery and apply a 6-cloth CHG regimen to all skin, except the face and genitals, a minimum of 1 hour after showering. The topical skin preparation with the chlorhexidine cloths was repeated on the morning of surgery in the holding area immediately before surgery.

Describe control (treatment/procedure/test):
The surgical skin preparation, administration of prophylactic antibiotics, and environmental conditions in the operating room were the same in the intervention and control group.

Length of follow-up:

Not given (SSIs were determined if a patient’s wound met the criteria of the CDC within 30 days of the index surgical procedure.

Loss-to-follow-up:

Not given

Incomplete outcome data:

Unclear

Outcome measures and effect size (include 95%CI and p-value if available):

Primary THA
Infection Rate; %
Change from Previous Year
2008 1.54%
2009 0.36%; -76.91
2010 1.02%; 185.79
2011 0.37%; -63.92
2012 0.48%; 30.0
2013 0.30%; -37.41
2014 0.16%; -45.97

Malcolm et al (2016)

Type of study:
Retrospective observational study

Setting:

Hospital-based (Cleveland Clinic Foundation main campus. Hillcrest Hospital, Lutheran Hospital, Euclid Hospital)
Country:
United States of America (USA)

Source of funding:
Not mentioned

Inclusion criteria:

All patients who underwent primary THA or TKA between October 2011 and March 2014 were included in this study.

Exclusion criteria:

Patients were excluded if they underwent revision TJA.

Inclusion/exclusion criteria control group:
Patients were included in the control group if they did not undergo nasal culture for Staphylococcus aureus at least four days prior to TJA. Patients were excluded if they were found to be

undergoing revision TJA.

N total at baseline:

Intervention: 2291 (56.7%)

Control: 1751 (43.4%)

Important prognostic factors²:

Mean age (SD)
Intervention: 63.8 (11.2)
Control: 64.2 (12.0)
p-value = 0.24

Gender, n (%)

Intervention:
Female: 1352 (59%)
Male: 1051 (60%)

Control:
Female: 1051 (60%)
Male: 700 (40%)
 

Groups comparable at baseline?

Not comparable in Charlson Comoribity Index (p-value <0.01

Describe intervention (treatment/procedure/test):

Patients were screened by sampling the nasal flora with

a nasal swab and subsequent analysis with either PCR testing or bacterial cultures up to four weeks before surgery. Approximately

one week prior to surgery, patients who carried S.

aureus were treated with topical mupirocin twice daily for three days. All patients in the study used chlorhexidine body wipes preoperatively and received appropriate perioperative antibiotic prophylaxis. Patients not carrying MRSA received

weight-based intravenous cefazolin 30 to 60 minutes preoperatively followed by repeated postoperative doses every eight hours for 24 hours. Patients who carried MRSA were administered weight-based vancomycin preoperatively followed by repeated postoperative doses every twelve hours for 24 hours. Those allergic to cephalosporin were administered

either clindamycin or vancomycin in a similar manner.

Describe control (treatment/procedure/test):
All patients in the study used chlorhexidine body wipes preoperatively and received appropriate perioperative antibiotic prophylaxis. Patients not carrying MRSA received

weight-based intravenous cefazolin 30 to 60 minutes preoperatively followed by repeated postoperative doses every eight hours for 24 hours. Patients who carried MRSA were administered weight-based vancomycin preoperatively followed by repeated postoperative doses every twelve hours for 24 hours. Those allergic to cephalosporin were administered either clindamycin or vancomycin in a similar manner.

Length of follow-up:

Not given (at least one year)

Loss-to-follow-up:

Not given

Incomplete outcome data:

Unclear

Outcome measures and effect size (include 95%CI and p-value if available):
Total revision:
Intervention group: 22 (1.0%)

Control group: 25 (1.4%)
p-value = 0.17

Reason for revision:

Prosthetic joint infection:
Intervention group: 9 (0.4%)

Control group: 16 (0.9%)
p-value = 0.04

Mechanical failure:
Intervention group: 13 (0.6%)
Control group: 9 (0.5%)
p-value = 1.0

Patients were included in the control group if they did not underwent screening. The reason why they did not underwent screening is not given in the studies.

Rao et al (2011)

Type of study:
Prospective observational study

Setting:

Hospital-based

Country:
United States of America (USA)

Source of funding:
Not funded

Inclusion criteria:

Not given (Its only written that patients in the intervention and preintervention control group were treated by the same surgeons. All patients who were treated by the other surgeons were included in the concurrent control group. In addition, all 741 patients whose surgery was performed by the 3 participating surgeons between October 2004 and October 2005 served as a preintervention control group)

Exclusion criteria:

Not given

N total at baseline:

Intervention group: 1440
Concurrent control group: 2284
Preintervention control group: 741

Important prognostic factors²:

No baseline values given

Groups comparable at baseline?

Not possible to assess

Describe intervention (treatment/procedure/test):

Patients were screened for S aureus nasal carriage two to four weeks before surgery.

Patients were educated

about the rationale for nasal cultures, and informed

consent was obtained. Samples were collected from both nares on a single swab (BBL Culture Swab Plus; BD

Diagnostics, Sparks, MD). The inside circumference of each anterior nares was rubbed for 3 to 5 seconds to

obtain adequate sampling. Specimens were inoculated

onto BBL CHROMagar MRSA and CHROMagar SA plates (BD Microbiology Systems, Sparks, MD), which were incubated for 20 to 28 hours at 35°C to 37°C. After 24 hours, we interpreted mauve colonies present on both

plates as MRSA and on only the CHROMagar SA plate as

MSSA. Negative plates were incubated for an additional

24 hours. Mauve colonies present on either medium at

48 hours were verified as S aureus by Gram stain and

coagulase testing (Staphaurex; Remel, Lenexa, KS). Mauve colonies growing on both media were reported

as MRSA, whereas colonies growing only on CHROMagar

SA were reported as MSSA. Approximately 1 week before surgery, patients with nasal cultures positive for S aureus were educated about the rationale for the decolonisation protocol, which was

performed in the outpatient setting. Patients were

instructed to apply mupirocin nasal ointment twice

daily to both nares and to bathe with chlorhexidine daily for 5 days immediately before the scheduled surgery.

During surgery, all patients received perioperative antibiotic prophylaxis. The standard regimen was cefazolin

2 g administered 30 to 60 minutes before surgery

followed by 1 g every 8 hours for 24 hours. The alternative regimen for patients with a history of MRSA infection or type I allergy to penicillin and for MRSA carriers in the intervention group was vancomycin 1 g 60

minutes before surgery followed by 1 g every 12 hours for 24 hours.

Describe control (treatment/procedure/test):
It is not written what the treatment was of patients in the control group.

Length of follow-up:

Two years

Loss-to-follow-up:

The study mentioned no lost to follow-up, but 155 patients in the intervention group missed screening.

Incomplete outcome data:

Unclear

Outcome measures and effect size (include 95%CI and p-value if available):

No. of SSIs in patients with positive nasal cultures confirmed (intervention group) and in the concurrent control group
Intervention = 0
Concurrent control = 19

Surgical Site Infections among patients who underwent TJA by the same group of orthopaedic surgeons during the preintervention period and intervention period:
MSSA = 3
MRSA = 2
Others = 6
Preintervention period:
MSSA = 3
MRSA = 8
Others = 9

Type of infection (type intervention / n preintervention period or intervention period):

Preintervention period:
Risk of superficial infections 11/741 (1.5%)
Risk of deep infections:
9/741 (1.2%)
Total:
20/741 (2.7%)

Intervention period:
Risk of superficial infections: 9/1440 (0.6%)
Risk of deep infections:
8/1440 (0.6%)
Total:
20/741 (2.7%)

It is written that all patients were prospectively monitored for development of SSIs.

Schweizer et al. (2016)

Type of study:
A quasi-experimental study

Setting:

Hospital-based

Country:
United States of America (USA)

Source of funding:
This project was funded by the

Agency for Healthcare Research and Quality

(AHRQ; HHSA2902006100021I and grant

HS022467-02), US Department of Health and

Human Services. It also received support from the

VA Health Services Research and Development

(CDA 11-211; Dr Schweizer).

Inclusion criteria intervention group:

Eligible patients were 18 years or older and underwent scheduled, urgent, or emergent primary hip or knee

arthroplasty (ie, replacement or resurfacing).

Exclusion criteria intervention group:

Arthroplasty revisions, cardiac transplants,

transapical valve implantation, and operations performed

using percutaneous or thoracotomy approaches were

not eligible for this study. We excluded operations among patients

with pre-existing infections at the surgical site.

Inclusion/exclusion criteria control group:

Only mentioned that hospitals

using some, but not all, bundle elements during the preintervention

period could participate.

N total at baseline:

Intervention group: 20642 operations
Control group: 11059 operations

Important prognostic factors²:

Sex:
Preintervention group:
Female: 12661 (61.4)
Intervention group:
Female: 6734 (60.9)
p-value = 0.41

Age, median (range)
Preintervention group: 68 (21 to 107)
Intervention group: 68 (18 to 101)
p-value <0.001
 
Groups comparable at baseline?

Not comparable in age, CCI and MRSA history

Describe intervention (treatment/procedure/test):

Hospital staff swabbed patients’ nares during scheduled preoperative

clinic visits (usually 10 to 14 days, but no more than 30

days before the operations). Each laboratory used their standard tests (eg, polymerase chain reaction, culture on chromogenic

agar, standard bacterial culture) to determine MRSA and MSSA carrier status. The most common tests were chromogenic agar for MRSA and standard culture for MSSA. Patients with positive screening tests for either MRSA or MSSA applied

mupirocin intranasally twice daily and bathed with CHG

once daily for up to 5 days immediately before their operations. Patients that received fewer than 10 doses of mupirocin before their operations received the remaining doses during

the postoperative period. The CHG bathing was not

continued after the operation. Patients with negative MRSA and

MSSA nasal screens bathed with CHG the night before and the morning of their operations. Perioperative prophylaxis was administered using weight based

dosing and redosing according to the 2013 American Society

of Health-System Pharmacists (ASHP) guidelines. The

antimicrobial agents used for perioperative prophylaxis varied by the patients’ S aureus carrier status; noncarriers and MSSA carriers received either cefazolin or cefuroxime for perioperative prophylaxis, whereas MRSA carriers received both cefazolin or cefuroxime and vancomycin. If a patient had a confirmed

β-lactam allergy, surgeons were encouraged to provide

perioperative prophylaxis with vancomycin rather than

cefazolin or cefuroxime and to add either gentamicin or aztreonam for gram-negative coverage. Patients with negative screening tests but with documented histories of MRSA carriage or infection were treated as carriers. Patients who were either not screened because they had emergent operations or

whose screening results were not known at the time of their operations received vancomycin and cefazolin or cefuroxime for perioperative prophylaxis. In these situations, nasal swabs

were obtained for MSSA and MRSA screening and patients began the decolonisation regimen immediately before their operations. Mupirocin was continued until screening test results were

known; mupirocin was discontinued if test results

were negative.

Describe control (treatment/procedure/test):
The preintervention period extended from March 1, 2009, to the date on which a hospital began the intervention.

Length of follow-up:

Patients were followed up for 90 days after their operations by

infection preventionists at participating hospitals.

Loss-to-follow-up:

Not given

Incomplete outcome data:

Unclear

Outcome measures and effect size (include 95%CI and p-value if available):


Complex Staphylococcus aureus Surgical Site Infections per 10000 operations

Rate ratio for Bundled Intervention (95% CI) (intervention period vs preintervention period)

Hip or knee arthroplasties
RR 0.48 (95%CI 0.29 – 0.80)
p-value = 0.005

Urgent/emergent
RR 0l.44 (0.07 – 2.72)
p-value = 0.38

Scheduled
RR 0.51 (0.30 – 0.85)
p-value = 0.009

Hospitals that using some, but not all bundle elements during the preintervention period could participate.

Its not mentioned in the study how patients were followed up by infection preventionists.

Stambough et al. (2016)

Type of study:
Retrospective review of prospective data

Setting:

Hospital-based

Country:
United States of America (USA)

Source of funding:
Its mentioned in the article that one or more of the authors of this paper have disclosed potential or pertinent conflicts of interest, which may include receipt of payment, either direct or indirect, institutional support, or association with an entity in the biomedical field which may be perceived to have potential conflict of interests with this work.

Inclusion criteria:

Cohort of patients from the academic medical center’s infection surveillance program who underwent elective primary hip or knee arthroplasty between March 1, 2011 and July 31, 2015. Patients were divided in 2 cohorts based on the 25 months before (control group) and the 25 months after establishment of the universal decolonisation protocol (intervention group).

Exclusion criteria:

Patients were excluded when they were admitted via the emergency department. Patients with prior instrumentation who were undergoing revision or conversion arthroplasty were also excluded.
Patients treated in the 3 months surrounding the protocol change were removed to control for potential treatment bias during the transition period.

N total at baseline (n= 4186 replacements):

Intervention group (2205 TJA in 2049 patients):
TKA: 1003
THA: 1202

Control group (1981 TJA in 1846 patients):
TKA: 836
THA: 1145

Important prognostic factors²:

Age (y mean±SD):
Control group: 57.2±14.1
Intervention group: 58.2±13.5
(χ² = 0.08)
 
Gender (n male):
Control group: 548
Intervention group: 558
(χ² = 0.025)

Groups comparable at baseline?

Yes (only not in ASA)

Describe intervention (treatment/procedure/test):

Patients in the intervention group were screened within 30 days of their surgery. Swabs of both nares were obtained and sent to the laboratory. All patients were treated with 2% nasal ointment and a single preoperative chlorhexidine shower. At the day of surgery, all nasal screening results were available. Carriers of MRSA were perioperative treated with Vancomycin 1 gram every 12 hours starting at least 30 minutes before incision and lasting for 24 hours. The surgical technique, implants and postoperative care were similar in both groups. In addition to preoperative mupirocin nasal ointment and chlorhexidine scrub, all patients were administered IV antibiotics within 1 our before surgical incision. Antibiotic selection was based on a risk stratification protocol and was continued for 24 hours postoperatively. The majority of patients received a weight-based dose of IV cefazolin – 2g for those with a weight <120 kg and 3 g if >120 kg. Those with a true penicillin allergy were given 1 g of vancomycin and 1 g of IV aztreonam to cover both gram-positive and gram-negative microbes. Additionally, patients who resided in a nursing facility, were on dialysis, had been hospitalized within the past year, or had a documented history of MRSA infection from an unrelated previous admission were administered IV vancomycin in addition to weight-based cefazolin.

Describe control (treatment/procedure/test):
Patients in the control group were all screened for S aureus colonization and selectively treated preoperatively with 5 days mupirocin. Patients were treated with a CHG wipes at the day of surgery.

Length to follow-up:
90 days

Loss-to-follow-up:
Not given

Incomplete outcome data:

Unclear

Outcome measures and effect size (include 95%CI and p-value if available):
Total number of SSI infections (THA+TKA):
Control group: 15 (0,8%)
Intervention group: 5 (0,2%)
(P-value = 0.013)

Infection caused by MRSA or MSSA (THA+TKA):
Control group: 10 (0.5%)
Intervention group: 2 (0.09%)
(P-value = 0.01)

Infection caused by MRSA (THA+TKA):
Control group: 6 (0.3%)
Intervention group: 1 (0.04%)
(P-value = 0.05)

Total number of SSI infections (THA):
Control group: 9
Intervention group: 2
(P-value = 0.03)

Infection caused by MRSA or MSSA (THA):
Control group: 7
Intervention group: 0
(P-value = 0.003)

Infection caused by MRSA (THA):
Control group: 4
Intervention group: 0
(P-value = 0.05)

 

Study reference

(first author, year of publication)

Bias due to a non-representative or ill-defined sample of patients?¹

(unlikely/likely/unclear)

Bias due to insufficiently long, or incomplete follow-up, or differences in follow-up between treatment groups?²

(unlikely/likely/unclear)

Bias due to ill-defined or inadequately measured outcome ?³

(unlikely/likely/unclear)

Bias due to inadequate adjustment for all important prognostic factors?⁴

(unlikely/likely/unclear)

Baratz et al. (2015)

Unclear

Unclear

Unclear

Likely

Sporer et al. (2016)

Unclear

Unclear

Unclear

Likely

Malcolm et al. (2016)

Unclear

Unclear

Unclear

Likely

Rao et al. (2011)

Unclear

Likely

Unclear

Likely

Schweizer et al. (2016)

Unclear

Unclear

Unclear

Unlikely

Stambough et al. (2016)

Unlikely

Unclear

Unclear

Likely