Consensus statement the Toronto Consensus for the Treatment of Helicobacter pylori Infection in Adults



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Reprint requests



Address requests for reprints to: Carlo A. Fallone, MD, Division of

Gastroenterology, McGill University Health Centre, Royal Victoria Hospital

Site, 1001 Decarie Boulevard, Room D5.7154, Montréal, Quebec, Canada

H4A 3J1. e-mail:

carlo.fallone@mcgill.ca

.

Acknowledgments



The consensus group thanks Paul Sinclair (Canadian Association of

Gastroenterology [CAG] representative, administrative and technical support)

and Louise Hope and Lesley Marshall (CAG, logistics assistance) as well as

Pauline Lavigne and Steven Portelance (unaf

filiated), who provided medical

writing services supported entirely by funds from CAG and the Canadian

Helicobacter Study Group.

The steering committee (CAF, NC, SVvZ), GIL, and PM reviewed the

literature and drafted the statements. GIL and PM assessed the evidence

and provided GRADE evaluations. All members of the CAG Treatment of H

pylori Infection Consensus Group voted on the recommendations. The

steering committee then drafted the initial manuscript, which was reviewed,

revised, and approved by all members of the consensus group and all

authors. It was subsequently made available to all CAG members for

comments before submission for publication.

CAG Statement

These consensus statements on the treatment of H pylori infection were

developed under the direction of Drs Carlo A. Fallone, Naoki Chiba, and

Sander Veldhuyzen van Zanten, in accordance with the policies and

procedures of CAG and under the direction of CAG Clinical Affairs. They

have been reviewed by the CAG Practice Affairs and Clinical Affairs

Committees and the CAG Board of Directors. The consensus statements

were developed following a thorough consideration of medical literature and

the best available evidence and clinical experience. They represent the

consensus of a Canadian and international panel composed of experts on

this topic. The consensus aims to provide a reasonable and practical

approach to care for specialists and allied health professionals obliged with

the duty of bestowing optimal care to patients and families and can be

subject to change as scienti

fic knowledge and technology advance and as

practice patterns evolve. These consensus statements are not intended to

be a substitute for physicians using their individual judgment in managing

clinical care in consultation with the patient, with appropriate regard to all

the individual circumstances of the patient, diagnostic and treatment options

available, and available resources. Adherence to these recommendations will

not necessarily produce successful outcomes in every case.

Con

flicts of interest



The authors disclose the following: Advisory Board: AbbVie (JPG), Allergan

(JPG), Almirall (JPG), AstraZeneca (JPG), Casen Fleet (JPG), Casen Recordati

(JPG), Chiesi (JPG), Dr Falk Pharma (JPG), Faes Farma (JPG), Ferring

Pharmaceuticals (JPG), Gebro Pharma (JPG), Hospira (JPG), Janssen (JPG),

Kern Pharma (JPG), MSD (JPG), Nycomed (JPG), Otsuka Pharmaceuticals

(JPG), P


fizer (JPG), Shire Pharmaceuticals (JPG), Takeda (JPG), Vifor Pharma

(JPG).


Consultation Fees: AbbVie (JKM, SVvZ), Actavis (CAF), AstraZeneca (JKM),

Celltrion (JKM), Cubist (JKM), Ferring Pharmaceuticals (JKM), Forest (JKM),

Hospira (JKM), Janssen (CAF, JKM, SVvZ), Procter & Gamble (JKM),

Pendopharm (CAF), Shire (JKM, SVvZ), Takeda (CAF, JKM).

Educational Support: AstraZeneca (PM).

Research Grants/Clinical Trial Funding: AbbVie (JPG), Allergan (JPG), Almirall

(JPG), AstraZeneca (JPG), Casen Fleet (JPG), Casen Recordati (JPG), Chiesi

(JPG), Dr Falk Pharma (JPG), Faes Farma (JPG), Ferring Pharmaceuticals

(JPG), Gebro Pharma (JPG), Hospira (JPG), Janssen (JPG), Kern Pharma

(JPG), MSD (JPG), Nycomed (JPG), Otsuka Pharmaceutical (JPG), P

fizer

(JPG), Shire Pharmaceuticals (JPG), Takeda (JPG), Vifor Pharma (JPG).



Speaker

’s Bureau: AbbVie (JPG, JKM), Allergan (JPG), Almirall (JPG), Aptalis

(JKM), AstraZeneca (JPG), Casen Fleet (JPG), Casen Recordati (JPG), Chiesi

(JPG), Dr. Falk Pharma (JPG), Faes Pharma (JPG), Ferring Pharmaceuticals

(JPG, JKM), Forest (JKM), Gebro Pharma (JPG), Hospira (JPG), Janssen

(JPG, JKM), Kern Pharma (JPG), MSD (JPG), Nycomed (JPG), Otsuka

Pharmaceutical (JPG), P

fizer (JPG), Procter & Gamble (JKM), Purdue Pharma

(SVvZ), Shire (JPG, JKM), Takeda (JPG, JKM, SVvZ), Warner Chilcott (JKM),

Vifor Pharma (JPG).

Funding

Supported by the Canadian Association of Gastroenterology and the Canadian



Helicobacter Study Group, with no external funding sources.

July 2016

Toronto Consensus for

H pylori Treatment

69


Supplementary Appendix 1. Search

Strategies Used for EMBASE,

MEDLINE, and CENTRAL

1. pylori.tw.

2. clarithromycin.tw.

3. (amoxicillin or amoxycillin).tw.

4. azithromycin.tw.

5. tetracycline.tw.

6. (roxithromycin or erythromycin).tw.

7. nitroimidazole.tw.

8. metronidazole.tw.

9. tinidazole.tw.

10. ranitidine-bismuth.tw

11. levo


floxacin*.tw.

12. moxi


floxacin*.tw.

13. furazolidone.tw.

14. rifabutin.tw.

15. or/2-14

16. 1 and 15

17. eradicat*.tw.

18. 1 and 17

19. 16 or 18

20. limit 19 to yr

¼2008-2013

21. exp animals/not humans.sh.

22. 20 not 21

23. limit 22 to english language

69.e1


Fallone et al

Gastroenterology Vol. 151, No. 1



Supplementary Table 1.Evidence for Statement 1 (In patients with H pylori infection, we recommend a treatment duration of 14 days)

Quality assessment

Summary of

findings


Comments

Studies


Risk

of bias


Inconsistency Indirectness Imprecision

Other


considerations

a

Quality



of evidence

Overall


quality

of evidence

Eradication rates

(ITT) (%)

Relative

effect


(95% CI)

Longer


duration

Shorter


duration

Eradication of H pylori infection (importance of outcome: critical for decision making)

PPI-based triple regimens: 14 days vs 7 days

4442


Moderate

The quality of

evidence is

moderate


for PAC

but low for

PMC

1 SR


28

(45 RCTs)

Serious

b

None



None

None


None

4442


Moderate

81.9


72.9

NNT: 11


(9

–14)


PPI-based triple

regimens: 14 days

vs 10 days

1 SR


28

(12 RCTs)

Serious

b

None



None

None


None

4442


Moderate

84.4


78.5

NNT: 17


(11

–46)


PPI-based triple

regimens: 10 days

vs 7 days

1 SR


28

(24 RCTs)

Serious

b

None



None

None


None

4442


Moderate

79.9


75.7

NNT: 21


(15

–38)


PPI-based triple regimens: 14 days vs 10 days vs 7 days

Increased

ef

ficacy


with longer

durations

of therapy

in resistant

strains

1 RCT


46

None


None

None


Serious

None


4442

Moderate


NA

NA

NA



PBMT: 14 days

vs 7 days

4222

Very low


Trend favoring

14 or 10 vs

7 days but

not


statistically

signi


ficant

1 SR


28

(3 RCTs)


Serious

b

None



None

Very serious

None

4222


Very low

77.9


69.1

Nonsigni


ficant

difference

PBMT: 14 days

vs 10 days

1 SR

28

(1 RCT)



Serious

b

None



None

Very serious

None

4222


Very low

91.6


92.6

Nonsigni


ficant

difference

1 SR

c

(cohort-type



data

from 51 studies)

None

Serious


None

Serious


None

4222


Very low

78.7


75.6

Nonsigni


ficant

difference

PBMT: 10 days

vs 7 days

1 SR

28

(2 RCTs)



Serious

b

None



None

Very serious

None

4222


Very low

87.4


81.9

Nonsigni


ficant

difference

July

2016


Toronto

Consensus

for

H

pylori



Treatment

69.e2


Supplementary Table 1. Continued

Quality assessment

Summary of

findings


Comments

Studies


Risk

of bias


Inconsistency Indirectness Imprecision

Other


considerations

a

Quality



of evidence

Overall


quality

of evidence

Eradication rates

(ITT) (%)

Relative

effect


(95% CI)

Longer


duration

Shorter


duration

PAMC


4222

Very low


1 SR

44

(cohort-type



data

from 15 studies)

None

None


None

Serious


None

4222


Very low

92 (10


days)

89 (5


days)

Not statistically

signi

ficant


1 cohort study

45

Serious



None

Serious


d

None


None

4222


Very low

93.3


(14 days)

86.6 (10


days)

P

< .01

Relative

effect not

reported

PAL: 14 days vs 7

days

4222


Very low

1 SR


28

(2 RCTs)


Serious

e

None



Serious

f

Serious



None

4222


Very low

78.5 (14


days)

42 (7


days)

NNT: 3


(2

–10)


SR, systematic review; NA, not applicable.

a

Including publication bias.



b

Most of the included RCTs were at high risk or unclear risk of bias.

c

Unpublished data; SR conducted for the meeting.



d

The longer regimen also included a higher PPI dose.

e

Both studies were at high risk for bias.



f

One of the studies used o

floxacin (not levofloxacin).

69.e3


Fallone

et

al



Gastroenterology

Vol.


151,

No.


1

Supplementary Table 2.Evidence for Statement 2 (In patients with H pylori infection, we recommend that the choice of

first-line therapy consider regional antibiotic

resistance patterns and eradication rates)

Quality assessment

Summary of

findings


Comments

Studies


Risk

of bias Inconsistency Indirectness Imprecision

Other

considerations



a

Quality


of evidence

Overall


quality

of evidence

Eradication rates (ITT)

Relative


effect

(95% CI)


Regional

antibiotic

resistance

patterns


considered

Regional


antibiotic

resistance

patterns not

considered

Eradication of H pylori infection (importance of outcome: critical for decision making)

Culture-guided vs empirical triple therapy

4422

Low


Culture-guided triple therapy

resulted in a signi

ficantly

lower risk of treatment



failure compared with

empirical standard triple

therapy

1 systematic



review

47

(5 RCTs)



Serious

b

None



Serious

c

None



None

4422


Low

NA

NA



NA

Time trends for H pylori antibiotic resistance and ef

ficacy of eradication regimens

Multiple


reviews of

observational

studies

19,22


None

None


Serious

None


None

4222


Very low

NA

NA



NA

a

Including publication bias.



b

Mainly due to inadequate sequence generation and unclear/inadequate allocation concealment.

c

The research question is only indirectly related to this statement.



July

2016


Toronto

Consensus

for

H

pylori



Treatment

69.e4


Supplementary Table 3. Evidence for Statement 3 (In patients with H pylori infection, we recommend traditional bismuth quadruple therapy [PBMT] for 14 days as one of

the options for

first-line therapy)

Quality assessment

Summary of

findings


Comments

Studies


Risk

of bias Inconsistency Indirectness Imprecision

Other

considerations



a

Quality of

evidence

Overall


quality of

evidence


Eradication rates (ITT) (%)

Relative


effect

(95% CI)


PBMT

Comparator

Eradication of H pylori infection (importance of outcome: critical for decision making)

Ef

ficacy: relative to PPI-based triple regimens



4442

Moderate


Trend toward higher

eradication (

w9%)

found in the SR



was signi

ficant


only in the per-

protocol analysis

(not ITT)

1 SR


22

(12 RCTs)

Serious

b

None



Serious

c

None



None

4422


Low

81.9


72.9

(PPI-based

triple

regimens)



Nonsigni

ficant


difference

1 RCT


61

None


None

None


Serious

None


4442

Moderate


70.0 (PBMT

for 14


days)

57.5 (PAC

for 14 days)

Nonsigni


ficant

difference

Ef

ficacy: absolute rates



Adequately high

eradication rate

SR of observational

studies and

observational-type

data from RCTs

22

None


None

None


None

None


4422

Low


77.6

NA

NA



Ef

ficacy: metronidazole-resistant strains

Metronidazole

resistance had

less impact on the

success of PBMT

regimens

compared with

clarithromycin

resistance on PAC

regimens

1 SR


21

(2 RCTs)


None

None


Serious

Serious


None

4422


Low

NA

NA



NA

Duration: PBMT for 14 days vs PBMT for 7 days

4222

Very low


Trends toward

superiority of

prolonged

duration vs 7 days

(not signi

ficant)


1 SR

28

(3 RCTs)



Serious

None


None

Very serious

None

4222


Very low

77.9


69.1

Nonsigni


ficant

difference

Duration: PBMT for 14 days vs PBMT for 10 days

1 SR


28

(1 RCT)


Serious

None


None

Very serious

None

4222


Very low

91.6


92.6

Nonsigni


ficant

difference

1 SR

d

(cohort-type



data from 51

studies)


None

Serious


Serious

e

Serious



None

4222


Very low

78.7


75.6

Nonsigni


ficant

difference

Duration: PBMT for 10 days vs PBMT for 7 days

1 SR


28

(2 RCTs)


Serious

None


None

Very serious

None

4222


Very low

87.4


81.9

Nonsigni


ficant

difference

a

Including publication bias.



b

Mainly due to lack of blinding.

c

The studies have tested regimens of various durations (7, 10, 14 days). No subgroup analyses for 14-day regimens were performed.



d

Unpublished data; SR conducted for the meeting.

e

The comparisons were between studies, not within study.



69.e5

Fallone


et

al

Gastroenterology



Vol.

151,


No.

1


Supplementary Table 4.Evidence for Statement 4 (In patients with H pylori infection, we recommend concomitant nonbismuth quadruple therapy [PAMC] for 14 days as

one of the options for

first-line therapy)

Quality assessment

Summary of

findings


Comments

Studies


Risk

of bias Inconsistency Indirectness Imprecision

Other

considerations



a

Quality of

evidence

Overall


quality of

evidence


Eradication rates (ITT) (%)

Relative


effect

(95% CI)


PAMC

Comparator

Eradication of H pylori infection (importance of outcome: critical for decision making)

Ef

ficacy: relative to PPI triple regimens



4442

Moderate


PAMC was superior

to PPI triple

therapy

1 SR


44

(6 RCTs)


Serious

b

None



None

None


None

4442


Moderate

91.1


80.6

Odds ratio,

2.4 (1.63

–3.55)


Ef

ficacy: relative to sequential regimen

PAMC was superior

to sequential

therapy

1 SR


69

(19 RCTs)

Serious

b

None



None

None


None

4442


Moderate

Not


reported

Not


reported

RD, 0.11


(0.07

–0.16)


Ef

ficacy: relative to hybrid regimen

c

2 RCTs


139,140

Serious


b

None


None

None


None

4442


Moderate

91.7


(for 14-day

treatment)

90.0

(for 14-day



treatment)

Nonsigni


ficant

difference

Ef

ficacy: absolute rates



Adequately high

eradication rate

1 SR

44

(cohort-type



data from

15 studies)

None

None


None

None


None

4422


Low

90

NA



NA

Duration: longer-duration PAMC or shorter-duration PAMC

4222

Very low


Trend favoring

longer duration

in SR (not

signi


ficant)

1 SR


44

(cohort-type

data from

15 studies)

None

None


None

Serious


None

4222


Very low

92

(10 days)



89 (5 days)

Not


statistically

signi


ficant

1 cohort study

45

None


None

Serious


d

Serious


None

4222


Very low

93.3


(14 days)

86.6 (10 days) P



< .01 Relative

effect not

reported

a

Including publication bias.



b

Mainly due to lack of blinding.

c

Hybrid regimen was omeprazole 40 mg and amoxicillin 1 g twice daily for 14 days plus clarithromycin 500 mg and nitroimidazole 500 mg twice daily for the



final 7 days.

d

The longer regimen also included a higher PPI dose.



July

2016


Toronto

Consensus

for

H

pylori



Treatment

69.e6


Supplementary Table 5.Evidence for Statement 5 (In patients with H pylori infection, we recommend restricting the use of PPI triple therapy [PAC or PMC for 14 days] to

areas with known low clarithromycin resistance [



<15%] or proven high local eradication rates [>85%])

Quality assessment

Summary of

findings


Comments

Studies


Risk

of bias Inconsistency Indirectness Imprecision

Other

considerations



a

Quality of

evidence

Overall


quality of

evidence


Eradication rates (ITT) (%)

Relative


effect

(95% CI)


PPI triple

therapy


Comparator

Eradication of H pylori infection (Importance of outcome: critical for decision making)

Ef

ficacy: relative to bismuth quadruple regimen (PBMT)



4442

Moderate


Low success rates

1 SR


22

(12 RCTs)

Serious

b

None



Serious

c

None



None

4422


Low

72.9


81.9

Nonsigni


ficant

difference

1 RCT

61

None



None

None


Serious

None


4442

Moderate


57.5

(PAC for


14 days)

70.0


(PBMT for

14 days)


Nonsigni

ficant


difference

Low success rates

Ef

ficacy: relative to sequential regimen



1 SR

70

(7 RCTs)



Serious

d

Serious



e

None


None

None


4442

Moderate


81.3

80.8


Nonsigni

ficant


difference

Ef

ficacy: relative to concomitant regimen



PPI triple therapy was

inferior to

concomitant

therapy


1 SR

44

(6 RCTs)



Serious

b

None



None

None


None

4442


Moderate

80.6


91.1

Odds ratio, 2.4

(1.63

–3.55)


Ef

ficacy: absolute rates

Low success rates

1 SR


22

(observational-type

data from 5 RCTs

published from

2006 to 2011)

None


None

None


None

None


4422

Low


61.5

NA

Duration: 14 days vs 7 days



4442

Moderate


The quality of evidence

is moderate for PAC

but low for PMC

1 SR


28

(45 RCTs)

Serious

f

None



None

None


None

4442


Moderate

81.9


72.9

NNT: 11 (9

–14)

Duration: 14 days vs 10 days



1 SR

28

(12 RCTs)



Serious

b

None



None

None


None

4442


Moderate

84.4


78.5

NNT: 17


(11

–46)


Culture-guided vs empirical triple therapy

4422


Low

Indirect evidence

1 SR

47

(5 RCTs)



Serious

g

None



Serious

h

None



None

4422


Low

NA

NA



NA

Time trends for H pylori resistance to clarithromycin and ef

ficacy of eradication regimens

Multiple reviews of

observational

studies


19,22

None


None

Serious


None

None


4222

Very low


NA

NA

NA



a

Including publication bias.

b

Mainly due to lack of blinding.



c

The studies have tested regimens of various durations (7, 10, 14 days). No subgroup analyses for 14-day regimens were performed.

d

None of the studies were at low risk for bias.



e

Unexplained heterogeneity.

f

Most of the included RCTs were at high risk or unclear risk of bias.



g

Mainly due to inadequate sequence generation and unclear/inadequate allocation concealment.

h

The research question is only indirectly related to this statement.



69.e7

Fallone


et

al

Gastroenterology



Vol.

151,


No.

1


Supplementary Table 6.Evidence for Statement 6 (In patients with H pylori infection, we recommend against the use of levo

floxacin triple therapy [PAL] as a first-line therapy)

Quality assessment

Summary of

findings

Comments


Studies

Risk


of bias Inconsistency Indirectness Imprecision

Other


considerations

a

Quality of



evidence

Overall


quality of

evidence


Eradication rates (ITT) (%)

Relative


effect

(95% CI)


PAL

Comparator

Eradication of H pylori infection (IMPORTANCE OF OUTCOME: CRITICAL for decision making)

Ef

ficacy: relative to PAC



4222

Very low


3 RCTs

78,79,81


Serious

b

Serious



c

None


Serious

None


4222

Very low


85, 80, and 81,

respectively

79, 64, and 87,

respectively

Overall,

nonsigni


ficant

difference

Ef

ficacy: levofloxacin-resistant strains



Signi

ficantly lower

eradication rates

with PAL in

levo

floxacin-


resistant vs

levo


floxacin-

sensitive strains

2 studies

(cohort-type

data from

2 RCTs)


52,81

None


None

Serious


None

None


4222

Very low


NA

NA

NA



a

Including publication bias.

b

Mainly due to lack of blinding.



c

Two of the RCTs showed better ef

ficacy for PAL, but the third showed better efficacy for PAC.

Supplementary Table 7.Evidence for Statement 7 (In patients with H pylori infection, we recommend against the use of sequential nonbismuth quadruple therapy [PA

followed by PMC] as a

first-line therapy)

Quality assessment

Summary of

findings

Comments


Studies

Risk


of bias Inconsistency Indirectness Imprecision

Other


considerations

a

Quality of



evidence

Overall


quality of

evidence


Eradication rates (ITT) (%)

Relative


effect

(95% CI)


Sequential

therapy


Comparator

Eradication of H pylori infection (importance of outcome: critical for decision making)

Ef

ficacy: relative to 14-day PPI triple regimens



4442

Moderate


1 SR

70

(7 RCTs)



Serious

b

None



None

None


None

4442


Moderate

81.3


80.8

Nonsigni


ficant

difference

Ef

ficacy: relative to concomitant nonbismuth quadruple therapy (PAMC)



Concomitant therapy

superior to

sequential therapy

1 SR


69

(14 RCTs) Serious

c

None


None

None


None

4442


Moderate

79.7


85.7

RD, 0.06


(0.03

–0.09)


Ef

ficacy: relative to traditional bismuth quadruple therapy (PBMT)

1 SR

70

(5 RCTs)



Serious

b

None



None

None


None

4442


Moderate

84.9


86.2

Nonsigni


ficant

difference

a

Including publication bias.



b

None of the studies was at low risk of bias.

c

Mainly due to lack of blinding.



July

2016


Toronto

Consensus

for

H

pylori



Treatment

69.e8


Supplementary Table 8.Evidence for Statement 8 (In patients who have previously failed to respond to H pylori eradication therapy, we recommend traditional bismuth

quadruple therapy [PBMT] for 14 days as an option for subsequent therapy)

Quality assessment

Summary of

findings

Comments


Studies

Risk


of bias Inconsistency Indirectness Imprecision

Other


considerations

a

Quality of



evidence

Overall


quality of

evidence


Eradication rates (ITT) (%)

Relative


effect

(95% CI)


PBMT

Comparator

Eradication of H pylori infection (importance of outcome: critical for decision making)

Ef

ficacy: absolute rates



4422

Low


Adequately high

eradication rate

after failure of

PPI triple therapy

1 SR (38 studies:

observational

studies and

observational-type

data from RCTs)

99

None



None

None


None

None


4422

Low


78

NA

NA



Duration: PBMT for 14 days vs PBMT for 10 days

Trend favoring 14

days (not

signi


ficant)

1 SR (14 studies:

observational

studies and

observational-type

data from RCTs)

99

None


None

Serious


b

Serious


None

4222


Very low

82

77



Nonsigni

ficant


difference

1 SR


c

(cohort-type

data from 51

studies)


None

Serious


Serious

b

Serious



None

4222


Very low

78.7


75.6

Nonsigni


ficant

difference

a

Including publication bias.



b

The comparisons were between studies, not within study.

c

Unpublished data; SR conducted for the meeting.



69.e9

Fallone


et

al

Gastroenterology



Vol.

151,


No.

1


Supplementary Table 9.Evidence for Statement 9 (In patients who have previously failed to respond to H pylori eradication therapy, we suggest levo

floxacin-containing

therapy for 14 days as an option for subsequent therapy)

Quality assessment

Summary of

findings


Comments

Studies


Risk

of bias


Inconsistency Indirectness Imprecision

Other


considerations

a

Quality of



evidence

Overall


quality of

evidence


Eradication rates (ITT) (%)

Relative


effect

(95% CI)


PAL

Comparator

Eradication of H pylori infection (importance of outcome: critical for decision making)

Ef

ficacy: relative to bismuth quadruple regimen (PBMT) after failure of PPI triple therapy



4422

Low


Adequately high

eradication

rates for

salvage


treatment

1 SR


99

(6 RCTs)


Serious

b

None



None

Serious


None

4422


Low

79

c



69

Nonsigni


ficant

difference

Ef

ficacy: absolute rates with 10-day PAL after failure of concomitant nonbismuth quadruple therapy



1 SR

105


(observational

type data from

3 studies)

Not known

d

Serious


e

None


Serious

None


4422

Low


78

NA

Ef



ficacy: absolute rates after failure of sequential nonbismuth quadruple therapy

1 SR


99

(observational

type data from

5 studies)

None

None


None

None


None

4422


Low

81

NA



NA

Duration: 10 days vs 7 days

4222

Very low


Superiority

of longer

duration

1 SR


106

(observational

type data

from 11 studies)

Not known

d

None



None

Serious


f

None


4222

Very low


88.7

70.6


P

< .05

Relative


effect not

reported


a

Including publication bias.

b

Mainly due to lack of blinding.



c

Calculated from unweighted means, but given that the weights of the included studies were very similar, it is likely that weighted estimates would produce similar results.

d

The SR did not report assessments of risk of bias.



e

Unexplained heterogeneity.

f

The comparisons were between studies, not within study.



July

2016


Toronto

Consensus

for

H

pylori



Treatment

69.e10


Supplementary Table 10.Evidence for Statement 10 (In patients who have previously failed to respond to a clarithromycin-containing H pylori eradication therapy, we

recommend against the use of clarithromycin-containing regimens as subsequent therapy)

Quality assessment

Summary of

findings

Comments


Studies

Risk


of bias Inconsistency Indirectness Imprecision

Other


considerations

a

Quality of



evidence

Overall


quality of

evidence


Eradication rates (ITT)

Relative


effect

(95% CI)


NA

NA

Eradication of H pylori infection (importance of outcome: critical for decision making)



Prevalence of secondary resistance to clarithromycin

4422


Low

The prevalence of

secondary resistance to

clarithromycin is very

high (up to 70%)

Multiple cohort

studies and

case series

20,40

None


None

None


None

None


4422

Low


NA

NA

NA



Impact of clarithromycin resistance

The ef


ficacy of

clarithromycin-

containing regimens is

highly affected by

clarithromycin

resistance

Multiple reviews

of observational

studies

19,22


None

None


Serious

None


None

4222


Very low

NA

NA



NA

a

Including publication bias.



Supplementary Table 11.Evidence for Statement 11 (In patients who have previously failed to respond to a levo

floxacin-containing H pylori eradication therapy, we

recommend against the use of levo

floxacin-containing regimens as subsequent therapy)

Quality assessment

Summary of

findings

Comments


Studies

Risk


of bias Inconsistency Indirectness Imprecision

Other


considerations

a

Quality of



evidence

Overall


quality of

evidence


Eradication rates (ITT) Relative

effect


(95% CI)

NA

NA



Eradication of H pylori infection (importance of outcome: critical for decision making)

Prevalence of secondary resistance to levo

floxacin

4422


Low

The prevalence of

secondary resistance to

levo


floxacin is very high

(up to 60%)

2 cohort studies

and case series

83,84

None


None

None


None

None


4422

Low


NA

NA

NA



Impact of levo

floxacin resistance

The ef

ficacy of


levo

floxacin-containing

regimens is highly

affected by levo

floxacin

resistance



2 studies (cohort-type

data from 2 RCTs)

52,81

None


None

Serious


None

None


4222

Very low


NA

NA

NA



a

Including publication bias.

69.e11

Fallone


et

al

Gastroenterology



Vol.

151,


No.

1


Supplementary Table 12. Evidence for Statement 12 (In patients who have previously failed to respond to H pylori eradication therapy, we recommend against the use of

sequential nonbismuth quadruple therapy [PA followed by PMC] as an option for subsequent therapy)

Quality assessment

Summary of

findings

Comments


Studies

Risk


of bias Inconsistency Indirectness Imprecision

Other


considerations

a

Quality of



evidence

Overall


quality of

evidence


Eradication rates (ITT) (%)

Relative


effect

(95% CI)


Sequential

therapy


Comparator

Eradication of H pylori infection (importance of outcome: critical for decision making)

Ef

ficacy: absolute rates



4222

Very low


2 cohort

studies


109,110

None


None

None


Very serious

b

None



4222

Very low


93 and 100

NA

Ef



ficacy: relative to concomitant nonbismuth quadruple therapy (PAMC) as first-line treatment

PAMC was superior

to sequential

therapy


1 SR

69

(19 RCTs) Serious



c

None


None

Very serious

d

None


4222

Very low


Not reported

Not reported

RD, 11%

(0.7%


–16%)

a

Including publication bias.



b

Forty and 2 patients, respectively.

c

Mainly due to lack of blinding.



d

These studies tested the regimens as

first-line treatments.

July


2016

Toronto


Consensus

for


H

pylori


Treatment

69.e12


Supplementary Table 13.Evidence for Statement 13 (We recommend restricting the use of rifabutin-containing regimens to cases in which at least 3 recommended

options have failed)

Quality assessment

Summary of

findings

Comments


Studies

Risk


of bias Inconsistency Indirectness Imprecision

Other


considerations

a

Quality of



evidence

Overall


quality of

evidence


Eradication rates (ITT) (%)

Relative


effect

(95% CI)


Rifabutin-

containing

regimens

Comparator

Eradication of H pylori infection (importance of outcome: critical for decision making)

Ef

ficacy: absolute rates (overall)



4222

Very low


Reasonable

eradication rate

for those who

previously failed

to respond to

therapy


1 SR

111


(21 studies: cohort

studies and

observational-type

data from RCTs)

None

None


Serious

b

None



None

4222


Very low

73

NA



NA

Ef

ficacy: absolute rates (4th- or 5th-line treatment)



4222

Very low


Eradication

demonstrated

when used as

fourth- or

fifh-

line therapy



1 SR

111


(7 studies: cohort

studies and

observational-type

data from RCTs)

None

None


None

None


Serious

4222


Very low

70

NA



NA

Duration: 10

–12 days vs 7 days (2nd-line treatment)

4222


Very low

Evidence suggests

more than 7

days is preferred

1 SR

111


(8 studies: cohort

studies and

observational-type

data from RCTs)

None

None


Very serious

c

None



Serious

4222


Very low

92

69



Not

reported


a

Including publication bias.

b

Included studies that tested the regimen as



first-, second-, third, fourth-, or fifth-line treatment.

c

Only second-line treatment; between-studies comparisons.



69.e13

Fallone


et

al

Gastroenterology



Vol.

151,


No.

1


Supplementary Table 14. Evidence for Statements 14 and 15 (In patients with H pylori infection, we recommend against routinely adding probiotics to eradication therapy

for the purpose of reducing adverse events or increasing eradication rates)

Quality assessment

Summary of

findings

Comments


Studies

Risk


of bias

Inconsistency Indirectness Imprecision

Other

considerations



a

Quality of

evidence

Overall


quality of

evidence


Eradication rates (ITT)

Relative


effect

(95% CI)


Probiotic

supplementation Comparator

Eradication of H pylori infection (importance of outcome: critical for decision making)

Effect on adverse effects

4222

Very low


Very low-quality

evidence


1 SR

126


(10 RCTs)

Serious


b

Serious


c

Serious


d

None


None

4222


Very low

Not reported

Not reported

Odds ratio,

2.1 (1.4

–3.1)


Effect on eradication rates

4222


Very low

Very low-quality

evidence

1 SR


126

(10 RCTs)

Serious

b

Serious



c

Serious


d

None


None

4222


Very low

Not reported

Not reported

Odds ratio,

0.3 (0.1

–0.8)


a

Including publication bias.

b

Mainly due to lack of blinding.



c

Unexplained heterogeneity.

d

Most of the studies assessed the impact of probiotic supplementation when added to triple rather than quadruple therapy.



July

2016


Toronto

Consensus



for

H

pylori



Treatment

69.e14

Document Outline

  • The Toronto Consensus for the Treatment of Helicobacter pylori Infection in Adults
    • Methods
      • Scope and Purpose
      • Sources and Searches
      • Review and Assessment of Evidence
      • Consensus Process
      • Role of the Funding Sources
    • Recommendation Statements
      • All Patients
        • Key evidence (Supplementary Table 1)
        • Decisions
      • First-Line Therapy
        • Statement 2. In patients with H pylori infection, we recommend that the choice of first-line therapy consider regional anti ...
        • Statement 3. In patients with H pylori infection, we recommend traditional bismuth quadruple therapy (PBMT) for 14 days as  ...
          • Key evidence (Supplementary Table 3)
          • Other issues and discussion
          • Decisions
        • Statement 4. In patients with H pylori infection, we recommend concomitant nonbismuth quadruple therapy (PAMC) for 14 days  ...
          • Key evidence (Supplementary Table 4)
          • Other issues and discussion
          • Decisions
        • Statement 5. In patients with H pylori infection, we recommend restricting the use of PPI triple therapy (PAC or PMC for 14 ...
          • Key evidence (Supplementary Table 5)
          • Other issues and discussion
          • Decisions
        • Statement 6. In patients with H pylori infection, we recommend against the use of levofloxacin triple therapy (PAL) as a fi ...
          • Key evidence (Supplementary Table 6)
          • Other issues and discussion
          • Decisions
        • Statement 7. In patients with H pylori infection, we recommend against the use of sequential nonbismuth quadruple therapy ( ...
          • Key evidence (Supplementary Table 7)
          • Other issues and discussion
          • Decisions
      • Prior Failure
        • Statement 8. In patients who have previously failed to respond to H pylori eradication therapy, we recommend traditional bi ...
          • Key evidence (Supplementary Table 8)
          • Other issues and discussion
          • Decisions
        • Statement 9. In patients who have previously failed to respond to H pylori eradication therapy, we suggest levofloxacin-con ...
          • Key evidence (Supplementary Table 9)
          • Other issues and discussion
          • Decisions
        • Statement 10. In patients who have previously failed to respond to clarithromycin-containing H pylori eradication therapy,  ...
          • Key evidence (Supplementary Table 10)
          • Decisions
        • Statement 11. In patients who have previously failed to respond to a levofloxacin-containing H pylori eradication therapy,  ...
          • Key evidence (Supplementary Table 11)
          • Decisions
        • Statement 12. In patients who have previously failed to respond to H pylori eradication therapy, we recommend against the u ...
          • Key evidence (Supplementary Table 12)
          • Decisions
        • Statement 13. We recommend restricting the use of rifabutin-containing regimens to cases in which at least 3 recommended op ...
          • Key evidence (Supplementary Table 13)
          • Other issues and discussion
          • Decisions
        • Other statements/comments
      • Supplemental Therapy
        • Statement 14. In patients with H pylori infection, we recommend against routinely adding probiotics to eradication therapy  ...
        • Statement 15. In patients with H pylori infection, we recommend against adding probiotics to eradication therapy for the pu ...
          • Key evidence (Supplementary Table 14)
          • Other issues and discussion
          • Decisions
    • Future Directions
    • Limitations of the Consensus
    • Summary
    • Supplementary Material
    • References
    • Acknowledgments
    • Supplementary Appendix 1. Search Strategies Used for EMBASE, MEDLINE, and CENTRAL

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