news & views
University Hospital, Freiburg and Praxiszentrum
fr Gastroenterologie, Bertoldstrasse 48,
Freiburg 79098, Germany.
martin-roessle@t-online.de
doi:10.1038/nrgastro.2010.147
Competing interests
The author declares no competing interests.
1. de Franchis, R. evolving consensus in portal
hypertension: report of the Baveno iv
consensus workshop on methodology of
diagnosis and therapy in portal hypertension.
J. Hepatol. 43, 167176 (2005).
2. Garcia-Pagan, J. C. et al. early use of TiPs in
patients with cirrhosis and variceal bleeding.
N. Engl. J. Med. 362, 23702379 (2010).
3. Goulis, J. et al. Bacterial infection is
independently associated with failure to control
bleeding in cirrhotic patients with
gastrointestinal hemorrhage. Hepatology 27,
12071212 (1998).
4. Ben-Ari, Z. et al. A predictive model for failure to
control bleeding during acute variceal bleeding.
J. Hepatol. 31, 443450 (1999).
infeCtion
Bismuth improves PPI-based triple
therapy for H. pylori eradication
Peter Malfertheiner
in a prospective Chinese study in which bismuth was added to standard
ppi-based triple therapy, the Helicobacter pylori eradication rate was
above 90%. increased treatment duration was also cruciala therapeutic
gain of 13% was achieved if the quadruple therapy was administered for
14 days instead of 7 days. Clarithromycin resistance was also overcome
by the prolonged bismuth-containing quadruple therapy.
Global guidelines recommend that firstline
therapies for Helicobacter pylori infection
should have a minimum 90% eradication
success rate. this eradication rate is fre
quently not achieved with the standard PPi
based triple therapies, primarily owing to
the increased prevalence of H. pylori strains
that are resistant to clarithromycin, and to a
lesser extent to metronidazole. a random
ized, openlabel Chinese trial including 160
patients with H. pylori infection and func
tional dyspepsia assessed whether adding
bismuth potassium citrate to the stan
dard twicedaily PPibased triple therapy
(omeprazole, amoxicillin and clarithro
mycin) and extending the treatment dura
tion from 7 days to 14 days would improve
treatment efficacy.1 the success rate of the
bismuthcontaining quadruple therapy in
the intentiontotreat analysis was 93.7% in
the 14day treatment arm versus 80.0%
in the 7day treatment arm (perprotocol
analysis; 97.4% and 82.0%, respectively).
538 | OCTOBER 2010 | vOlumE 7
5. Rssle, M. & Grandt, D. TiPs: an update. Best
Pract. Res. Clin. Gastroenterol. 18, 99123
(2004).
6. Luca, A. et al. TiPs for prevention of recurrent
bleeding in patients with cirrhosis: meta-
analysis of randomized clinical trials. Radiology
212, 411421 (1999).
7. DAmico, G., Pagliaro, L. & Bosch, J. The
treatment of portal hypertension: a meta-
analytic review. Hepatology 22, 332354
(1995).
8. Chalasani, n. et al. Determinants of mortality in
patients with advanced cirrhosis after
transjugular intrahepatic portosystemic
shunting. Gastroenterology 118, 138144
(2000).
9. Rajan, D. K., Haskal, Z. J. & Clark, T. w. serum
bilirubin and early mortality after transjugular
intrahepatic portosystemic shunts: results of a
multivariate analysis. J. Vasc. Interv. Radiol. 13
(Pt 1), 155161 (2002).
10. Groszmann, R. J. et al. Beta-blockers to prevent
gastroesophageal varices in patients with
cirrhosis. N. Engl. J. Med. 353, 22542261
(2005).
sun and colleagues, who performed the
study, did not include a control group who
were treated with standard triple therapy,
and this omission limits their ability to
prove the superiority of the quadruple
therapy over the standard triple therapy.
However, they refer to other studies per
formed in China that achieved eradication
rates of only around 75% with standard
triple therapy.2,3
A key finding is that
14 days of quadruple treatment
overcomes clarithromycin
resistance...
the optimal duration of PPibased triple
therapy with amoxicillin and clarithromycin
is an ongoing matter of debate. although
study results are contradictory they are gen
erally not in favor of a prolonged treatment
duration. 4,5 For example, a prospective,
2010 Macmillan Publishers Limited. All rights reserved
randomized trial found no therapeutic
gain from extending standard triple therapy
from 7 days to 14 days.6 However, this is not
the case for the bismuthenhanced triple
therapy (quadruple therapy), which pro
vides a therapeutic gain of more than 10%
if treatment is prolonged from 7 days to
14 days.1
a key finding from the Chinese study is
that 14 days of quadruple treatment over
comes clarithromycin resistance in the major
ity of patients (84.6%), whereas the 7day
treatment does not (36.3%). although the
number of patients with clarithromycin
resistant strains of H. pylori in the study was
small (24 patients), this is a relevant finding,
as it indicates that the addition of colloi
dal bismuth to a firstline regimen would
maintain the high eradication efficacy
when treating antibioticresistant strains.
in addition, monitoring for the develop
ment of clarithromycin resistance would
not be required and bismuthcontaining
quadruple therapy could even compen
sate for the absence of new, alternative
anti biotics. However, coll oidal bismuth
might be even more effective if added to a
regimen containing metronidazole instead
of clarithromycin. this strategy should
totally eliminate the issue of clarithromycin
resistance. metronidazole resistance is
less relevant; as it has a stable resistance
pattern over many years, shortterm expo
sure to high doses of metronidazole (up to
1,600 mg) is not expected to carry a high
risk of severe adverse effects. the addition
of bismuth and prolonged treatment dura
tion seem to be effective for the eradication
of H. pylori infection.
sequential therapy as an alternative
approach to overcoming clarithromycin
resistance has been advocated. in sequen
tial therapy, a PPi plus amoxicillin given for
5 days is followed by a PPi, clarithromycin
and metronidazole for a further 5 days.
this sequential form of quadruple therapy
is consistently superior to the standard first
line triple therapy.7 However, nearly all the
successful studies have been performed in
just one european country (italy), which
limits the wide promotion of sequential
quadruple therapy as a viable approach to
clarithromycin resistance. the superiority
of sequential quadruple therapy over stan
dard triple therapy has also yet to be con
firmed in other parts of the world, such as
the asian Pacific region.8
Quadruple therapies have a long tradi
tion as a secondline therapy, but have also
been proven effective as a firstline therapy.
www.nature.com/nrgastro

in fact, quadruple therapy is recommended
as a firstline option in regions where
clarithromycin resistance is >15%.9 sun and
colleagues used a quadruple therapy that
retains the antibiotics used in standard triple
therapyclarithromycin and amoxicillin.
this approach differs from the classic quad
ruple therapy, which contains tetracycline
and metronidazole. in the usa, a new
galenic capsule formulation of the classic
quadruple therapy has an efficacy similar
to that of standard triple therapy and does
largely overcome H. pylori metronidazole
resistance.10 sun et al. mention that adding
bismuth to the conventional triple therapy
might be better for avoiding adverse effects
associated with high doses of metronidazole,
as used in the classic quadruple therapy.
However, no evidence supports this theory
for shortterm treatment.
the addition of colloidal bismuth to
the standard triple therapy results in an
improved eradication rate, therefore,
bismuth is the key ingredient that makes
the difference. this effect is attributable
to bismuths synergistic effect with anti
biotics, particularly with the 5nitroimid
azole family of antibiotics, which includes
metronid azole.11 the study by sun et al.
clearly demonstrates that extending therapy
duration to 14 days is the other key factor
in the efficacy of bismuthcontaining quad
ruple therapy, leading to a therapeutic gain
of around 15%. this effect is particularly
pertinent in regions of high clarithro
mycin resistance. thus, it is the combina
tion of these factors that ultimately confers
high efficacy (>90% eradiation rate) to the
quadruple therapy.
the lesson learned from the study by
sun and colleagues is that prolongation of
eradication therapy beyond 7 days is impor
tant for the efficacy of quadruple therapy
with bismuth. in response to the world
wide increase in clarithromycin resistance,
quadruple therapies will have to be pro
moted from a secondline therapy option
to a firstline therapy option in regions
where clarithromycin resistance rises to
20% or higher. Future guidelines will have
to reconsider carefully firstline thera
peutic options and the inclusion of bismuth
potassium citrate in treatment regimens.
Otto-von-Guericke University, Department of
Gastroenterology, Hepatology and Infectious
Diseases, Leipziger Strasse 44, Magdeburg
39120, Germany.
peter.malfertheiner@med.ovgu.de
doi:10.1038/nrgastro.2010.131
nature reviews | gastroenterology & hepatology
Competing interests
The author declares associations with the following
companies: Axcan and novartis. see the article
online for full details of the relationships.
1. sun, Q. et al. High efficacy of 14-day triple
therapy-based, bismuth-containing quadruple
therapy for initial H. pylori eradication.
Helicobacter 15, 233238 (2010).
2. Mu, F., Hu, F., Yang, G. & Cheng, H. A clinical
study of proton pump inhibitor-containing
quadruple regimen as first-line therapy for
H. pylori eradication. Chin. J. Gastroenterol. 12,
531534 (2007).
3. Zheng, Q., Pan, Y., Zhang, L. & Xiao, s.
Comparison of efficacy of 7-day rabeprazole-
based triple therapy versus quadruple therapy
for treatment of H. pylori infection. Chin. J.
Gastroenterol. 11, 645647 (2006).
4. Calvet, X., Gen, e., Lpez, T. & Gisbert, J. P.
what is the optimal length of proton pump
inhibitor-based triple therapies for H. pylori?
A cost-effectiveness analysis. Aliment.
Pharmacol. Ther. 15, 10671076 (2001).
5. Fuccio, L. et al. Meta-analysis: duration of first-
line proton-pump inhibitor based triple therapy
for H. pylori eradication. Ann. Intern. Med. 147,
553562 (2007).
6. Zagari, R. M. et al. Comparison of 1 and
2 weeks of omeprazole, amoxicillin and
enDosCopy
Nitrous oxide sedation for
colonoscopyno laughing matter
Archana S. Rao and Todd H. Baron
Moderate sedation is typically used during lower gastrointestinal endoscopy
procedures. Deep sedation with propofol is becoming widespread but
carries the risk of cardiorespiratory depression. nitrous oxide is an inhaled
sedative administered routinely in dentistry that might prove to be a safe
option for sedation during lower gastrointestinal endoscopy.
moderate or conscious sedation has tradi
tionally been used for patients undergoing
gastrointestinal endoscopic procedures.
this level of sedation aims to reduce
patients anxiety, discomfort and memory
of the procedure while enabling them to
maintain independent cardiovascular and
pulmonary functioning and to provide
appropriate responses to verbal instruc
tions. typically, a combination of an opioid
analgesic and a benzodiazepine is utilized to
achieve this state.
over the past 1015 years, practice has
been shifting towards use of deep seda
tion for endoscopic procedures. a survey
of gastroenterologists (primarily from
private practice) in the us confirmed that
although opioids and benzodiazepines
remain the most common method of seda
tion for colonoscopy, a surprisingly high
2010 Macmillan Publishers Limited. All rights reserved
news & views
clarithromycin treatment for H. pylori
eradication: The HYPeR study. Gut 56,
475479 (2007).
7. Gatta, L., vakil, n., Leandro, G., Di Mario, F. &
vaira D. sequential therapy or triple therapy for
H. pylori infection: systematic review and meta-
analysis of randomized controlled trials in
adults and children. Am. J. Gastroenterol. 104,
30693079 (2009).
8. Moayyedi, P. & Malfertheiner, P. editorial:
sequential therapy for eradication of H. pylori:
a new guiding light or a false dawn? Am. J.
Gastroenterol. 104, 30813083 (2009).
9. Malfertheiner, P. et al. Current concepts in the
management of H. pylori infection: the
Maastricht iii Consensus Report. Gut 56,
772781 (2007).
10. Laine, L. et al. Bismuth-based quadruple
therapy using a single capsule of bismuth
biskalcitrate, metronidazole, and tetracycline
given with omeprazole versus omeprazole,
amoxicillin, and clarithromycin for eradication of
H. pylori in duodenal ulcer patients:
a prospective, randomized, mulicenter, north
American trial. Am. J. Gastroenterol. 98,
562567 (2003).
11. Goodwin, C. s. et al. Prevention of
nitroimidazole resistance in Campylobacter
pylori by coadministration of colloidal bismuth
subcitrate: clinical and in vitro studies. J. Clin.
Pathol. 41, 207210 (1988).
proportion (~26%) used propofol as their
preferred agent.1 the considerable empha
sis on propofol administration in the 2008
guidelines from the american society for
Gastrointestinal endoscopy (asGe) on
sedation for endoscopy also parallels this
practice trend.2 a comparable tendency is
evident in other worldwide regions; a recent
multicenter study conducted in 10 european
countries and Canada found that an average
of 30% of colonoscopies were performed
with deep sedation, primarily with the use of
propofol.3 the advantages of propofol seda
tion include quicker induction and recovery
times and perhaps a slight improvement in
patients satisfaction with the procedure
compared to standard sedation with intra
venous opioids and benzodiazepines.4 its
major disadvantage, however, is impair
ment of the patients cardiorespiratory
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