Peptic ulcer bleeding
The main modifiable risk factors for peptic ulcer bleeding are active Helicobacter pylori infection and the use of concurrent medications particularly cyclo-oxygenase (COX) inhibitors and antiplatelet agents.
Helicobacter pylori
It is well established that H. pylori
causes both complicated and uncomplicated duodenal and gastric ulcers
and that successful eradication of the organism alters the natural
history of the disease and prevents ulcer recurrence [Malfertheiner et al. 2012]. Although the prevalence of H. pylori
infection is possibly slightly lower in bleeding ulcers compared with
uncomplicated ulcers, it is also clear that removal of the infection
after a peptic ulcer bleed (PUB) episode prevents rebleeding. Rebleeding
remains a significant risk in the continued presence of H. pylori,
but eradication essentially abolishes this risk. A meta-analysis showed
that, with successful eradication, the rebleeding rate was 0.22% per
year [Gisbert et al. 2007], such that continued anti-ulcer therapy is not required in the absence of other risk factors.
causes both complicated and uncomplicated duodenal and gastric ulcers
and that successful eradication of the organism alters the natural
history of the disease and prevents ulcer recurrence [Malfertheiner et al. 2012]. Although the prevalence of H. pylori
infection is possibly slightly lower in bleeding ulcers compared with
uncomplicated ulcers, it is also clear that removal of the infection
after a peptic ulcer bleed (PUB) episode prevents rebleeding. Rebleeding
remains a significant risk in the continued presence of H. pylori,
but eradication essentially abolishes this risk. A meta-analysis showed
that, with successful eradication, the rebleeding rate was 0.22% per
year [Gisbert et al. 2007], such that continued anti-ulcer therapy is not required in the absence of other risk factors.
Although
the absolute rate of PUB after detection of an uncomplicated ulcer is
low, again successful eradication prevents bleeding [Sonnenberg et al. 1999]. Thus H. pylori
eradication provides an excellent intervention for primary and
particularly secondary prevention of PUB. The exact antibiotic regimens
used should be determined by local results and resistance patterns; in
the United Kingdom (especially where there are low levels of underlying
resistance to macrolides) a 7-day course of twice-daily proton pump
inhibitor (PPI), amoxicillin and clarithromycin remains very effective,
although in other regions 10- or 14-day regimens are indicated [Malfertheiner et al. 2012]. The recent Maastricht consensus guidelines provide excellent guidance on the suitable antibiotic choices [Malfertheiner et al. 2012].
Because eradication of the organism so effectively reduces rebleeding,
multiple courses of antibiotic therapies, guided if necessary by
antibiotic sensitivity data, should be employed to clear the organism.
the absolute rate of PUB after detection of an uncomplicated ulcer is
low, again successful eradication prevents bleeding [Sonnenberg et al. 1999]. Thus H. pylori
eradication provides an excellent intervention for primary and
particularly secondary prevention of PUB. The exact antibiotic regimens
used should be determined by local results and resistance patterns; in
the United Kingdom (especially where there are low levels of underlying
resistance to macrolides) a 7-day course of twice-daily proton pump
inhibitor (PPI), amoxicillin and clarithromycin remains very effective,
although in other regions 10- or 14-day regimens are indicated [Malfertheiner et al. 2012]. The recent Maastricht consensus guidelines provide excellent guidance on the suitable antibiotic choices [Malfertheiner et al. 2012].
Because eradication of the organism so effectively reduces rebleeding,
multiple courses of antibiotic therapies, guided if necessary by
antibiotic sensitivity data, should be employed to clear the organism.
The interaction of H. pylori with other risk factors is not as clear as might have been expected. In general, H. pylori
infection and aspirin or nonsteroidal anti-inflammatory agents (NSAIDs)
have independent and additive effects in increasing PUB [Huang et al. 2002; Malfertheiner et al. 2012]. In some patients, however, those who develop hypochlorhydria in response to H. pylori infection may be protective against ulceration [Iijima et al. 2012] and further complexity is added as the beneficial effect of acid suppression with PPIs may be enhanced by current H. pylori infection [Malfertheiner et al. 2012]. In clinical practice it is not usually feasible to detect into which group any one patient falls and H. pylori
is generally regarded as increasing the overall risk associated with
taking aspirin or NSAIDs, and so eradication is always advised.
infection and aspirin or nonsteroidal anti-inflammatory agents (NSAIDs)
have independent and additive effects in increasing PUB [Huang et al. 2002; Malfertheiner et al. 2012]. In some patients, however, those who develop hypochlorhydria in response to H. pylori infection may be protective against ulceration [Iijima et al. 2012] and further complexity is added as the beneficial effect of acid suppression with PPIs may be enhanced by current H. pylori infection [Malfertheiner et al. 2012]. In clinical practice it is not usually feasible to detect into which group any one patient falls and H. pylori
is generally regarded as increasing the overall risk associated with
taking aspirin or NSAIDs, and so eradication is always advised.
After an aspirin-induced PUB, in initially infected patients H. pylori eradication reduces rebleeding when aspirin is reintroduced (rebleeding rates at 6 months were 1.9% for H. pylori eradication alone and 0.9% for maintenance omeprazole alone [Chan et al. 2001]). Similarly Chan and colleagues [Chan et al. 2013] have also recently reported rebleeding rates after the reintroduction of low-dose aspirin to be lower in those who had had H. pylori
infection and eradication (0.97% per year) than those that were never
infected but had an aspirin-induced GI bleed (5.22% per year). For
comparison it should be noted that the bleeding rate in a control group
of new aspirin users without any ulcer history was 0.66% per year and
that none of the participants were prescribed antisecretory therapy.
After an aspirin-induced AUGIB, the rebleeding rate after aspirin
reintroduction following H. pylori eradication and with lansoprazole coprescription was 1.6% per year compared with 14.8% with eradication therapy alone [Lai et al. 2002]. So although H. pylori
eradication is of benefit after an aspirin-induced AUGIB bleed, the
protection is less than that seen with the combination of eradication
and maintenance PPI therapy. Therefore eradication should be regarded as
one essential element of secondary prevention in this situation.
infection and eradication (0.97% per year) than those that were never
infected but had an aspirin-induced GI bleed (5.22% per year). For
comparison it should be noted that the bleeding rate in a control group
of new aspirin users without any ulcer history was 0.66% per year and
that none of the participants were prescribed antisecretory therapy.
After an aspirin-induced AUGIB, the rebleeding rate after aspirin
reintroduction following H. pylori eradication and with lansoprazole coprescription was 1.6% per year compared with 14.8% with eradication therapy alone [Lai et al. 2002]. So although H. pylori
eradication is of benefit after an aspirin-induced AUGIB bleed, the
protection is less than that seen with the combination of eradication
and maintenance PPI therapy. Therefore eradication should be regarded as
one essential element of secondary prevention in this situation.
H. pylori
eradication before starting long-term antiplatelet therapy is
recommended, as this reduced ulceration but has not been definitively
shown to reduce bleeding [Malfertheiner et al. 2012].
eradication before starting long-term antiplatelet therapy is
recommended, as this reduced ulceration but has not been definitively
shown to reduce bleeding [Malfertheiner et al. 2012].
The situation regarding NSAIDs is even more complex. Eradication before starting NSAIDs is also recommended [Malfertheiner et al. 2012], this reduces but does not abolish NSAID-induced peptic ulcers (from 26% to 3% at 8 weeks and 34% to 12% at 6 months [Chan et al. 1997, 2002]) but once NSAIDs have been introduced there appears to be some mucosal adaptation and H. pylori eradication at that point in patients without ulcers may not offer significant protection [Vergara et al. 2005]. After a NSAID-induced PUB, H. pylori
eradication is inferior to maintenance omeprazole in reducing
rebleeding if NSAIDs are restarted (18.8% rebleeding at 6 months
compared with 4.4% [Chan et al. 2001]). Following a PUB, however, removal of all the different risk factors seems appropriate and H. pylori eradication is appropriate but is not a substitute for appropriate pharmacological secondary prevention.
eradication is inferior to maintenance omeprazole in reducing
rebleeding if NSAIDs are restarted (18.8% rebleeding at 6 months
compared with 4.4% [Chan et al. 2001]). Following a PUB, however, removal of all the different risk factors seems appropriate and H. pylori eradication is appropriate but is not a substitute for appropriate pharmacological secondary prevention.
It is important to appreciate that most diagnostic tests for H. pylori
perform less well in the situation of acute peptic ulcer bleeding. This
may be due to blood in the stomach or other factors but the exact
reasons remain unclear. The biopsy-based tests (urease, culture and
histopathology) all have significantly diminished sensitivity in acute
bleeding (sensitivities about 45–70%); faecal antigen testing
sensitivity is also reduced, although less so (sensitivity remains at
about 87%). Serology remains sensitive, although it is by nature less
specific for active infection [Gisbert and Abraira, 2006]. Urea breath testing appears to remains effective in the acute bleeding setting but can be logistically difficult to arrange [Gisbert and Abraira, 2006]. For these reasons the most recent Maastricht guidelines advocate empirical anti H. pylori therapy as soon as possible after PUB [Malfertheiner et al. 2012]. This strategy is particularly of benefit in areas with a high prevalence of H. pylori.
This has the advantages of maximizing early eradication and probably
reducing loses to follow-up diagnostic testing. However, this does leave
the dilemma of what to do after a negative follow-up test: has the
infection been cleared or was the patient never infected in the first
place? These situations require different management. The authors’
preference is for the alternative strategy, as outlined in the
Maastricht guidelines, particularly appropriate for low prevalence H. pylori areas, that is, performing diagnostic H. pylori
testing at the initial endoscopy and providing eradication if the tests
are positive. If tests are negative, performing a highly specific and
sensitive test (either faecal antigen or urea breath test) 6–8 weeks
after the acute episode after stopping any PPI therapy and then managing
appropriately.
perform less well in the situation of acute peptic ulcer bleeding. This
may be due to blood in the stomach or other factors but the exact
reasons remain unclear. The biopsy-based tests (urease, culture and
histopathology) all have significantly diminished sensitivity in acute
bleeding (sensitivities about 45–70%); faecal antigen testing
sensitivity is also reduced, although less so (sensitivity remains at
about 87%). Serology remains sensitive, although it is by nature less
specific for active infection [Gisbert and Abraira, 2006]. Urea breath testing appears to remains effective in the acute bleeding setting but can be logistically difficult to arrange [Gisbert and Abraira, 2006]. For these reasons the most recent Maastricht guidelines advocate empirical anti H. pylori therapy as soon as possible after PUB [Malfertheiner et al. 2012]. This strategy is particularly of benefit in areas with a high prevalence of H. pylori.
This has the advantages of maximizing early eradication and probably
reducing loses to follow-up diagnostic testing. However, this does leave
the dilemma of what to do after a negative follow-up test: has the
infection been cleared or was the patient never infected in the first
place? These situations require different management. The authors’
preference is for the alternative strategy, as outlined in the
Maastricht guidelines, particularly appropriate for low prevalence H. pylori areas, that is, performing diagnostic H. pylori
testing at the initial endoscopy and providing eradication if the tests
are positive. If tests are negative, performing a highly specific and
sensitive test (either faecal antigen or urea breath test) 6–8 weeks
after the acute episode after stopping any PPI therapy and then managing
appropriately.
COX inhibitors
It
is well established that COX inhibitors increase the risk of peptic
ulcer bleeding. Overall most standard nonspecific NSAIDs (nsNSAIDs)
increase the risk about 2–4-fold; bleeding rates are approximately
0.2–1.9% per year [Scheiman and Hindley, 2010; Garcia Rodriguez and Barreales Tolosa, 2007].
The basic paradigm underlying the gastroduodenal toxicity of
COX-inhibitors is the ‘COX-1 hypothesis’. The beneficial effects of COX
inhibitors in reducing pain and inflammation are due in inhibition of
the COX-2 inducible enzyme isoform, thus reducing the formation of
prostaglandins and prostacyclin that contribute to these
pathophysiological effects. The other isoform COX-1 is a constitutive
(‘housekeeping’) enzyme expressed in many tissues, including the GI
mucosa, where the produced prostaglandins contribute to the continued
health of the mucosa by regulating various functions including blood
flow and mucus secretion that contribute to ‘mucosal defence’. Thus
nsNSAIDs that inhibit both isoforms impair mucosal defence and lead to
ulceration. This paradigm is supported by clinical studies that show
that selective (sCOX-2) inhibitors are as effective as nsNSAIDs for pain
and inflammation [Chen et al. 2008] and that GI toxicity is generally inversely correlated with COX-2 selectively [Warner et al. 1999; Chang et al. 2011; Castellsague et al. 2009; Garcia Rodriguez, 1997].
However, GI toxicity and bleeding almost certainly have several other
determinants including the half-life of the drugs (damage increases with
half-life), effects on platelet function and the fact that COX-2
appears to be important in for ulcer healing [Peskar, 2001; Chatterjee et al. 2012; Garcia Rodriguez and Barreales Tolosa, 2007].
There are also experimental data showing that inhibition of both COX-1
and COX-2, but not one in isolation, are required to induce peptic
ulceration [Wallace et al. 2000]. Nevertheless, this model does provide a basis for developing strategies for prevention of PUB in COX inhibitor users.
is well established that COX inhibitors increase the risk of peptic
ulcer bleeding. Overall most standard nonspecific NSAIDs (nsNSAIDs)
increase the risk about 2–4-fold; bleeding rates are approximately
0.2–1.9% per year [Scheiman and Hindley, 2010; Garcia Rodriguez and Barreales Tolosa, 2007].
The basic paradigm underlying the gastroduodenal toxicity of
COX-inhibitors is the ‘COX-1 hypothesis’. The beneficial effects of COX
inhibitors in reducing pain and inflammation are due in inhibition of
the COX-2 inducible enzyme isoform, thus reducing the formation of
prostaglandins and prostacyclin that contribute to these
pathophysiological effects. The other isoform COX-1 is a constitutive
(‘housekeeping’) enzyme expressed in many tissues, including the GI
mucosa, where the produced prostaglandins contribute to the continued
health of the mucosa by regulating various functions including blood
flow and mucus secretion that contribute to ‘mucosal defence’. Thus
nsNSAIDs that inhibit both isoforms impair mucosal defence and lead to
ulceration. This paradigm is supported by clinical studies that show
that selective (sCOX-2) inhibitors are as effective as nsNSAIDs for pain
and inflammation [Chen et al. 2008] and that GI toxicity is generally inversely correlated with COX-2 selectively [Warner et al. 1999; Chang et al. 2011; Castellsague et al. 2009; Garcia Rodriguez, 1997].
However, GI toxicity and bleeding almost certainly have several other
determinants including the half-life of the drugs (damage increases with
half-life), effects on platelet function and the fact that COX-2
appears to be important in for ulcer healing [Peskar, 2001; Chatterjee et al. 2012; Garcia Rodriguez and Barreales Tolosa, 2007].
There are also experimental data showing that inhibition of both COX-1
and COX-2, but not one in isolation, are required to induce peptic
ulceration [Wallace et al. 2000]. Nevertheless, this model does provide a basis for developing strategies for prevention of PUB in COX inhibitor users.
Preventative strategies
The
available strategies, which are not mutually exclusive are: (1) reduce
gastroduodenal damage by coprescription of an acid suppressive agent;
(2) reintroduce the ‘missing’ mucosal prostaglandins by using the
prostaglandin analogue misoprostol; and (3) use COX inhibitors that more
selectively inhibit COX-2. Of these, misoprostol is rarely used (in the
MEDAL programme of COX inhibitor users, only 0.07% used misoprostol
compared with over 50% using acid suppression [Laine et al. 2007]).
Although misoprostol has the advantage of high quality clinical trial
data showing that it reduces peptic ulcer complications in NSAID users [Silverstein et al. 1995]
(and not just surrogate endoscopic or uncomplicated ulcer endpoints),
the side effect profile (over 20% get significant diarrhoea) and
requirement for multiple daily dosing probably limit its wider use [Targownik et al. 2008]. However, misoprostol is available as combined preparation with several NSAIDs and may have a role in certain patients.
available strategies, which are not mutually exclusive are: (1) reduce
gastroduodenal damage by coprescription of an acid suppressive agent;
(2) reintroduce the ‘missing’ mucosal prostaglandins by using the
prostaglandin analogue misoprostol; and (3) use COX inhibitors that more
selectively inhibit COX-2. Of these, misoprostol is rarely used (in the
MEDAL programme of COX inhibitor users, only 0.07% used misoprostol
compared with over 50% using acid suppression [Laine et al. 2007]).
Although misoprostol has the advantage of high quality clinical trial
data showing that it reduces peptic ulcer complications in NSAID users [Silverstein et al. 1995]
(and not just surrogate endoscopic or uncomplicated ulcer endpoints),
the side effect profile (over 20% get significant diarrhoea) and
requirement for multiple daily dosing probably limit its wider use [Targownik et al. 2008]. However, misoprostol is available as combined preparation with several NSAIDs and may have a role in certain patients.
By
relatively sparing mucosal COX-1, the sCOX-2 agents have a lower
incidence of gastrodudoenal ulceration and GI bleeding. Although the
sCOX-2 agents usually go under the umbrella of ‘-coxibs’, this belies
the complexity of the situation as some traditional nsNSAIDs are
relatively COX-2 specific (meloxicam, etodolac and nalbumetone) [Warner et al. 1999; Abraham et al. 2007].
Even within the coxibs there is a spread of COX-2 selectivity, the now
withdrawn rofecoxib and valdecoxib being significantly more selective
than the still available celecoxob and etoricoxib [Warner et al. 1999]. For the purpose of the prevention of PUB, the authors regard the latter two agents as clinically sCOX-2.
relatively sparing mucosal COX-1, the sCOX-2 agents have a lower
incidence of gastrodudoenal ulceration and GI bleeding. Although the
sCOX-2 agents usually go under the umbrella of ‘-coxibs’, this belies
the complexity of the situation as some traditional nsNSAIDs are
relatively COX-2 specific (meloxicam, etodolac and nalbumetone) [Warner et al. 1999; Abraham et al. 2007].
Even within the coxibs there is a spread of COX-2 selectivity, the now
withdrawn rofecoxib and valdecoxib being significantly more selective
than the still available celecoxob and etoricoxib [Warner et al. 1999]. For the purpose of the prevention of PUB, the authors regard the latter two agents as clinically sCOX-2.
The
greater acid suppression produced by PPIs provides greater protection
against NSAID-induced ulcers than that seen with standard doses of H2
receptor antagonists (H2RAs) [Lin et al. 2011; Lanas et al. 2007b]. Although double-dose H2RAs have greater protective effects than standard doses [Targownik et al. 2008; Rostom et al. 2009],
it is difficult to see how this is any advantage over single dose PPI.
PPIs prevent NSAID-induced ulceration in endoscopic and clinical studies
and large case-control studies have confirmed that PPI coprescription
reduces the risk of peptic ulcer bleeding by 50–80% and that this
effective reduction is seen against all combinations of risk factors [Lin et al. 2011; Lanas et al. 2007b].
Data from case-control studies suggest that PPI or sCOX-2 based
strategies may be more effective that misopostol-based strategies [Targownik et al. 2008].
Particularly now that generic PPIs are available, the simplest strategy
to prevent NSAID-induced PUB would be coprescription of PPI with all
COX-inhibitors. Economic modelling suggests that this is a
cost-effective strategy (Latimer et al. 2009)
and indeed the United Kingdom National Institute of Clinical Excellence
(NICE) has recommended PPI coprescription with all long-term use of
NSAIDs or sCOX-2 agents [NICE, 2008]. Despite the long-standing realization that NSAIDs cause PUB, it seems preventative strategies are underused [Lanas et al. 2011]
and a blanket policy should have the advantage of increasing
appropriate use of gastroprotection. Several fixed-dose combinations of
NSAIDs and PPIs are now available which may improve concordance.
greater acid suppression produced by PPIs provides greater protection
against NSAID-induced ulcers than that seen with standard doses of H2
receptor antagonists (H2RAs) [Lin et al. 2011; Lanas et al. 2007b]. Although double-dose H2RAs have greater protective effects than standard doses [Targownik et al. 2008; Rostom et al. 2009],
it is difficult to see how this is any advantage over single dose PPI.
PPIs prevent NSAID-induced ulceration in endoscopic and clinical studies
and large case-control studies have confirmed that PPI coprescription
reduces the risk of peptic ulcer bleeding by 50–80% and that this
effective reduction is seen against all combinations of risk factors [Lin et al. 2011; Lanas et al. 2007b].
Data from case-control studies suggest that PPI or sCOX-2 based
strategies may be more effective that misopostol-based strategies [Targownik et al. 2008].
Particularly now that generic PPIs are available, the simplest strategy
to prevent NSAID-induced PUB would be coprescription of PPI with all
COX-inhibitors. Economic modelling suggests that this is a
cost-effective strategy (Latimer et al. 2009)
and indeed the United Kingdom National Institute of Clinical Excellence
(NICE) has recommended PPI coprescription with all long-term use of
NSAIDs or sCOX-2 agents [NICE, 2008]. Despite the long-standing realization that NSAIDs cause PUB, it seems preventative strategies are underused [Lanas et al. 2011]
and a blanket policy should have the advantage of increasing
appropriate use of gastroprotection. Several fixed-dose combinations of
NSAIDs and PPIs are now available which may improve concordance.
A
blanket policy of PPI gastroprotection is not always advised, perhaps
due to cost, increased tablet burden or concerns about long-term use of
PPIs. In this situation it is possible to perform risk stratification to
inform choices regarding preventative strategies.
blanket policy of PPI gastroprotection is not always advised, perhaps
due to cost, increased tablet burden or concerns about long-term use of
PPIs. In this situation it is possible to perform risk stratification to
inform choices regarding preventative strategies.
Risk stratification for the use of COX-inhibitors and preventative strategies
Although
there are no universally validated scoring criteria, several factors
have consistently been shown to increase the risk of PUB associated with
NSAID use. These are outlined in Box 1.
Those outlined have the advantage of being biologically plausible and
both clinical relevant and easily measurable. There are alternative but
similar stratification strategies but in general, the more risk factors
the greater the risk of bleeding [Lanas et al. 2011, 2012],
although the absolute increase varies between populations and some
patient groups (such as rheumatoid arthritis) probably have an
independently increased risk of PUB.
there are no universally validated scoring criteria, several factors
have consistently been shown to increase the risk of PUB associated with
NSAID use. These are outlined in Box 1.
Those outlined have the advantage of being biologically plausible and
both clinical relevant and easily measurable. There are alternative but
similar stratification strategies but in general, the more risk factors
the greater the risk of bleeding [Lanas et al. 2011, 2012],
although the absolute increase varies between populations and some
patient groups (such as rheumatoid arthritis) probably have an
independently increased risk of PUB.
Box 1.
Risk factor stratification for acute GI haemorrhage in users of COX inhibitors or antiplatelet agents.
Lowest increase in risk
- Age < 65 years
- No other risk factors
Moderate increase in risk
One or two moderate risk factors:
- Age > 65 years
- In combination with another antiplatelet
- In combination with another NSAID
- In combination with oral bisphosphonate
- In combination with serotonin reuptake inhibitor
- In common with systemic corticosteroids
Highest risk
Three or more moderate risk factors OR any of:
COX, cyclo-oxygenase; GI, gastrointestinal; NSAID, nonsteroidal anti-inflammatory drug.
Therefore it is possible to determine three general groups at risk of NSAID-associated PUB and implement a strategy as shown in Table 1.
In the lowest risk group (younger patients without risk factors), many
authorities would suggest that preventative strategies are not mandatory
but that the least GI toxic drug in the lowest possible dose should be
used where possible. Ibuprofen appears to be associated with a lower
risk of PUB, and piroxicam and azapropazone the highest, with the other
nsNSAIDS somewhere in the middle, although there is considerable overlap
between the risks attributed to each agent [Henry et al. 1996; Chang et al. 2011; Castellsague et al. 2009; Garcia Rodriguez, 1997; Lanas et al. 2006].
In the lowest risk group (younger patients without risk factors), many
authorities would suggest that preventative strategies are not mandatory
but that the least GI toxic drug in the lowest possible dose should be
used where possible. Ibuprofen appears to be associated with a lower
risk of PUB, and piroxicam and azapropazone the highest, with the other
nsNSAIDS somewhere in the middle, although there is considerable overlap
between the risks attributed to each agent [Henry et al. 1996; Chang et al. 2011; Castellsague et al. 2009; Garcia Rodriguez, 1997; Lanas et al. 2006].
Guidance on suitable strategies for reducing acute GI haemorrhage in users of COX inhibitors with regard to cardiovascular risk.
The
group with modestly (but significantly) increased risk of AUGIB
encompasses those with one or two additional risk factors. Age per se
is probably not a risk factor for AUGIB alone but does exacerbate the
effects of NSAIDs or other risk factors. Some form of preventative
strategy is appropriate for this group and PPI coprescription with a
nsNSAID, a sCOX-2 agent alone or additional misoprostol and a nsNSAID
are all suitable. The large clinical trials performed for the launch of
the sCOX-2 agents showed that these drugs were associated with
significantly less uncomplicated ulcers [Bombardier et al. 2000; Laine et al. 2007; Silverstein et al. 2000].
Bleeding ulcers were less common and the studies failed to convincingly
show a significant reduction; however, subsequent case-control studies
have shown that sCOX-2 agents are associated with lower rates of
ulceration and PUB [Rostom et al. 2007, 2009; Lanas et al. 2007; Garcia Rodriguez and Barreales Tolosa, 2007].
Individual trials and a meta-analysis have shown that the separate ‘PPI
+ nsNSAID’ and ‘sCOX-2’ strategies are equivalent in reducing ulcer
complications [Rostom et al. 2009; Fosbol et al. 2010; Targownik et al. 2008; Lanas et al. 2007; Chan et al. 2002, 2004; Lai et al. 2005] and in a case-control study both were suggested to be more effective than misoprostol [Targownik et al. 2008].
Hence the choice of strategy in the moderately increased GI bleeding
risk group can be determined by other factors such as costs and presence
of reflux symptoms which might necessitate PPI therapy.
group with modestly (but significantly) increased risk of AUGIB
encompasses those with one or two additional risk factors. Age per se
is probably not a risk factor for AUGIB alone but does exacerbate the
effects of NSAIDs or other risk factors. Some form of preventative
strategy is appropriate for this group and PPI coprescription with a
nsNSAID, a sCOX-2 agent alone or additional misoprostol and a nsNSAID
are all suitable. The large clinical trials performed for the launch of
the sCOX-2 agents showed that these drugs were associated with
significantly less uncomplicated ulcers [Bombardier et al. 2000; Laine et al. 2007; Silverstein et al. 2000].
Bleeding ulcers were less common and the studies failed to convincingly
show a significant reduction; however, subsequent case-control studies
have shown that sCOX-2 agents are associated with lower rates of
ulceration and PUB [Rostom et al. 2007, 2009; Lanas et al. 2007; Garcia Rodriguez and Barreales Tolosa, 2007].
Individual trials and a meta-analysis have shown that the separate ‘PPI
+ nsNSAID’ and ‘sCOX-2’ strategies are equivalent in reducing ulcer
complications [Rostom et al. 2009; Fosbol et al. 2010; Targownik et al. 2008; Lanas et al. 2007; Chan et al. 2002, 2004; Lai et al. 2005] and in a case-control study both were suggested to be more effective than misoprostol [Targownik et al. 2008].
Hence the choice of strategy in the moderately increased GI bleeding
risk group can be determined by other factors such as costs and presence
of reflux symptoms which might necessitate PPI therapy.
Overall,
although sCOX-2 agents are safer from the GI point of view, they are
not completely risk free. In the colonic adenoma prevention trial,
rofecoxib was associated with a PUB rate of 0.23 per 100 patient years
(compared with 0.06 for placebo) [Lanas et al. 2007a]; however, most of this residual risk is ameliorated by PPI therapy [Lin et al. 2011].
In the highest GI risk group, with a previous NSAID-induced PUB,
neither a sCOX-2 alone nor a NSAID + PPI appear to offer sufficient
protection with 6-month rebleeding rates of 3.7–4.9% for the sCOX-2
celecoxib and 5.6–6.4% for nsNSAID plus PPI [Chan et al. 2002, 2004; Lai et al. 2005].
In this highest GI risk group, the optimal treatment if a COX-inhibitor
is to be continued is the combination of a sCOX-2 and a PPI. In a
well-designed randomized trial, rebleeding after NSAID-induced PUB was
significantly lower with celecoxib combined with esomprazole (0%)
compared with celecoxib alone (8.9%) [Chan et al. 2007]. This sCOX-2 plus PPI combination has also been shown to have the lowest risk of PUB in case control studies [Lin et al. 2011].
although sCOX-2 agents are safer from the GI point of view, they are
not completely risk free. In the colonic adenoma prevention trial,
rofecoxib was associated with a PUB rate of 0.23 per 100 patient years
(compared with 0.06 for placebo) [Lanas et al. 2007a]; however, most of this residual risk is ameliorated by PPI therapy [Lin et al. 2011].
In the highest GI risk group, with a previous NSAID-induced PUB,
neither a sCOX-2 alone nor a NSAID + PPI appear to offer sufficient
protection with 6-month rebleeding rates of 3.7–4.9% for the sCOX-2
celecoxib and 5.6–6.4% for nsNSAID plus PPI [Chan et al. 2002, 2004; Lai et al. 2005].
In this highest GI risk group, the optimal treatment if a COX-inhibitor
is to be continued is the combination of a sCOX-2 and a PPI. In a
well-designed randomized trial, rebleeding after NSAID-induced PUB was
significantly lower with celecoxib combined with esomprazole (0%)
compared with celecoxib alone (8.9%) [Chan et al. 2007]. This sCOX-2 plus PPI combination has also been shown to have the lowest risk of PUB in case control studies [Lin et al. 2011].
Cardiovascular toxicity of COX inhibitors
The
preventative management of PUB was dealt a serious blow by the
withdrawal from the market of the effective sCOX-2 agent rofecoxib
because of adverse cardiovascular effects (lumaricoxib was withdrawn
because of hepatic toxicity and valdecoxib primarily for skin
reactions). Whilst a blow to clinical therapeutics, this could be viewed
a proof of pharmacological principles. Normally platelets produce
thromboxane A2 (TXA2) via a COX-1 dependent pathway, which
enhances aggregation. This is balanced by endothelial production of
prostaglandins, predominantly prostacyclin (PGI2), which inhibits
aggregation. Inhibition of platelet COX-1 protects against thrombotic
episodes [Beales and Ogunwobi, 2010]. It has generally been thought that COX-2 was predominantly responsible for the production of PGI2 [Grosser et al. 2006],
it is not surprising that more selective inhibition of COX-2 tips the
balance in favour of platelet activation and increases the risk of
circulatory events. Additional mechanisms are probably involved in
increasing cardiovascular risk with coxibs, including altered renal
electrolyte handling, changes in vascular tone and altered myocardial
function and apoptosis [Grosser et al. 2006].
However although this ‘COX-1 platelets/COX-2 endothelium’ model seems
to explain the clinical observations and effects of sCOX-2, the
simplicity of this concept has been challenged principally by the
difficulty in detecting physiological expression of COX-2 in the
endothelium [Mitchell et al. 2006] and the finding that, experimentally, COX-1 seems to the predominant physiological source of circulating PGI2 [Kirkby et al. 2012].
Alternative mechanisms, including the specific ability to inhibit
vascular COX-1, may underlie the cardiovascular toxicity of NSAIDs [Mitchell et al. 2006].
preventative management of PUB was dealt a serious blow by the
withdrawal from the market of the effective sCOX-2 agent rofecoxib
because of adverse cardiovascular effects (lumaricoxib was withdrawn
because of hepatic toxicity and valdecoxib primarily for skin
reactions). Whilst a blow to clinical therapeutics, this could be viewed
a proof of pharmacological principles. Normally platelets produce
thromboxane A2 (TXA2) via a COX-1 dependent pathway, which
enhances aggregation. This is balanced by endothelial production of
prostaglandins, predominantly prostacyclin (PGI2), which inhibits
aggregation. Inhibition of platelet COX-1 protects against thrombotic
episodes [Beales and Ogunwobi, 2010]. It has generally been thought that COX-2 was predominantly responsible for the production of PGI2 [Grosser et al. 2006],
it is not surprising that more selective inhibition of COX-2 tips the
balance in favour of platelet activation and increases the risk of
circulatory events. Additional mechanisms are probably involved in
increasing cardiovascular risk with coxibs, including altered renal
electrolyte handling, changes in vascular tone and altered myocardial
function and apoptosis [Grosser et al. 2006].
However although this ‘COX-1 platelets/COX-2 endothelium’ model seems
to explain the clinical observations and effects of sCOX-2, the
simplicity of this concept has been challenged principally by the
difficulty in detecting physiological expression of COX-2 in the
endothelium [Mitchell et al. 2006] and the finding that, experimentally, COX-1 seems to the predominant physiological source of circulating PGI2 [Kirkby et al. 2012].
Alternative mechanisms, including the specific ability to inhibit
vascular COX-1, may underlie the cardiovascular toxicity of NSAIDs [Mitchell et al. 2006].
Further
studies have shown that all COX-inhibitors (except aspirin) are
associated with an increased risk of cardiovascular outcomes [Kearney et al. 2006; Abraham et al. 2007; Friedewald et al. 2010].
The mechanisms include those mentioned above due to COX-2 inhibition
but also complex and variable effects on platelet COX-1. Traditional
nsNSAIDs are reversible COX-1 inhibitors and do not seem to produce
clinically significant platelet inhibition. In addition several
nsNSAIDs, particularly ibuprofen, have been shown to impair the
antiplatelet action of aspirin by impairing access of aspirin to its
binding site on the active site of the enzyme [Awa et al. 2012; Catella-Lawson et al. 2001].
There are some data suggesting that the cardiovascular toxicity of
naproxen is less than that of comparable nsNSAIDs and sCOX-2 agents [McGettigan and Henry, 2011; Jick et al. 2006a, 2006b]; this may be explained by naproxen having a longer half-life [Strand, 2007]
and producing significant platelet inhibition itself. This has led to
naproxen being commonly advocated as the first-line NSAID in patients
with a baseline increased risk of cardiovascular disease [Abraham et al. 2010].
This is not without controversy as other studies have shown that,
although all COX-inhibitors were associated with an increased risk of
cardiovascular adverse effects and the risk correlated with COX-2
selectivity (being highest for rofecoxib the most selective agent),
naproxen itself was associated with a four-fold increased risk compared
with no treatment and this was not significantly lower than other
commonly used nsNSAIDs or even the moderately selective sCOX-2 (and the
authors included celecoxib in that group) [Abraham et al. 2007].
studies have shown that all COX-inhibitors (except aspirin) are
associated with an increased risk of cardiovascular outcomes [Kearney et al. 2006; Abraham et al. 2007; Friedewald et al. 2010].
The mechanisms include those mentioned above due to COX-2 inhibition
but also complex and variable effects on platelet COX-1. Traditional
nsNSAIDs are reversible COX-1 inhibitors and do not seem to produce
clinically significant platelet inhibition. In addition several
nsNSAIDs, particularly ibuprofen, have been shown to impair the
antiplatelet action of aspirin by impairing access of aspirin to its
binding site on the active site of the enzyme [Awa et al. 2012; Catella-Lawson et al. 2001].
There are some data suggesting that the cardiovascular toxicity of
naproxen is less than that of comparable nsNSAIDs and sCOX-2 agents [McGettigan and Henry, 2011; Jick et al. 2006a, 2006b]; this may be explained by naproxen having a longer half-life [Strand, 2007]
and producing significant platelet inhibition itself. This has led to
naproxen being commonly advocated as the first-line NSAID in patients
with a baseline increased risk of cardiovascular disease [Abraham et al. 2010].
This is not without controversy as other studies have shown that,
although all COX-inhibitors were associated with an increased risk of
cardiovascular adverse effects and the risk correlated with COX-2
selectivity (being highest for rofecoxib the most selective agent),
naproxen itself was associated with a four-fold increased risk compared
with no treatment and this was not significantly lower than other
commonly used nsNSAIDs or even the moderately selective sCOX-2 (and the
authors included celecoxib in that group) [Abraham et al. 2007].
However
given the high prevalence and serious sequelae of cardiovascular
adverse events, it is essential that this is factored into any strategy
to prevent PUB. A suggested plan is outlined in Table 2.
Patients can be divided into six groups depending on the presence of
high cardiovascular risk (usually defined as established cardiovascular
disease or a 10% probability of disease after 10 years by standard risk
calculators and/or low/intermediate/high risk of PUB (somewhat
heterogeneously but most easily defined as in Table 1 and Box 1
to facilitate clinically useful decisions). Those at low risk of
cardiovascular and GI events can receive a nsNSAID (additional PPI may
not be necessary), those at modestly increased risk of GI toxicity but
no increased cardiovascular risk a sCOX-2 (or nsNSAID + PPI, or nsNSAID +
misoprostol), and those at highest risk of GI events without increased
cardiovascular risk should receive a sCOX-2 plus PPI. Patients at
increased cardiovascular risk but intermediate GI risk are probably best
treated based on current evidence with naproxen + PPI (plus
cardioprotective aspirin as appropriate), whilst those with significant
cardiovascular and GI risks should ideally avoid all nonaspirin
COX-inhibitors [Abraham et al. 2010].
In practice this is a significant group and decisions will need to be
based on individual circumstances and perceived risks and benefits,
although as discussed below accruing data may inform these decisions.
given the high prevalence and serious sequelae of cardiovascular
adverse events, it is essential that this is factored into any strategy
to prevent PUB. A suggested plan is outlined in Table 2.
Patients can be divided into six groups depending on the presence of
high cardiovascular risk (usually defined as established cardiovascular
disease or a 10% probability of disease after 10 years by standard risk
calculators and/or low/intermediate/high risk of PUB (somewhat
heterogeneously but most easily defined as in Table 1 and Box 1
to facilitate clinically useful decisions). Those at low risk of
cardiovascular and GI events can receive a nsNSAID (additional PPI may
not be necessary), those at modestly increased risk of GI toxicity but
no increased cardiovascular risk a sCOX-2 (or nsNSAID + PPI, or nsNSAID +
misoprostol), and those at highest risk of GI events without increased
cardiovascular risk should receive a sCOX-2 plus PPI. Patients at
increased cardiovascular risk but intermediate GI risk are probably best
treated based on current evidence with naproxen + PPI (plus
cardioprotective aspirin as appropriate), whilst those with significant
cardiovascular and GI risks should ideally avoid all nonaspirin
COX-inhibitors [Abraham et al. 2010].
In practice this is a significant group and decisions will need to be
based on individual circumstances and perceived risks and benefits,
although as discussed below accruing data may inform these decisions.
Primary prevention of oesophageal variceal haemorrhage. (Adapted from AASLD guidelines [Garcia-Tsao et al. 2007].)
Interactions between aspirin and COX-2 inhibitors
There
are complex and incompletely understood interactions between aspirin
and COX inhibitors. As discussed above, probably all nonaspirin COX
inhibitors increase the risk of cardiovascular events and the
combination of aspirin and a COX inhibitor increases the risk of PUB [Lanas et al. 2006, 2012; Lin et al. 2011].
As may be expected from pharmacological principles, the addition of the
COX-1 inhibitor action of aspirin to a sCOX-2 negates the absolute
reduction in GI events seen compared with an nsNSAID alone [Silverstein et al. 2000; Rostom et al. 2009; Lanas et al. 2006],
and in view of this and the perceived cardiovascular toxicity of
sCOX-2, this combination is generally avoided. At the same time,
experimentally several nsNSAIDs and sCOX-2s impair the COX-1 inhibitory
action of aspirin and certainly ibuprofen impairs the antiplatelet
action in vivo [Rimon et al. 2010; Awa et al. 2012; Catella-Lawson et al. 2001].
This effect is seen if the ibuprofen is given prior or up to 1 hour
after aspirin but not if aspirin is given 2 hours before ibuprofen [Awa et al. 2012].
Noncompetitive binding of ibuprofen within the active site of COX-1,
thus preventing aspirin covalently binding to COX-1, is the likely
mechanism. Similar detailed interactions have not been explored for all
other nsNSAIDs, but when used in combination it may be wise to avoid
nsNSAID dosing prior to aspirin.
are complex and incompletely understood interactions between aspirin
and COX inhibitors. As discussed above, probably all nonaspirin COX
inhibitors increase the risk of cardiovascular events and the
combination of aspirin and a COX inhibitor increases the risk of PUB [Lanas et al. 2006, 2012; Lin et al. 2011].
As may be expected from pharmacological principles, the addition of the
COX-1 inhibitor action of aspirin to a sCOX-2 negates the absolute
reduction in GI events seen compared with an nsNSAID alone [Silverstein et al. 2000; Rostom et al. 2009; Lanas et al. 2006],
and in view of this and the perceived cardiovascular toxicity of
sCOX-2, this combination is generally avoided. At the same time,
experimentally several nsNSAIDs and sCOX-2s impair the COX-1 inhibitory
action of aspirin and certainly ibuprofen impairs the antiplatelet
action in vivo [Rimon et al. 2010; Awa et al. 2012; Catella-Lawson et al. 2001].
This effect is seen if the ibuprofen is given prior or up to 1 hour
after aspirin but not if aspirin is given 2 hours before ibuprofen [Awa et al. 2012].
Noncompetitive binding of ibuprofen within the active site of COX-1,
thus preventing aspirin covalently binding to COX-1, is the likely
mechanism. Similar detailed interactions have not been explored for all
other nsNSAIDs, but when used in combination it may be wise to avoid
nsNSAID dosing prior to aspirin.
The two major
questions on which clarity is needed to inform choices regarding the
clinical use of aspirin combined with NSAIDs concern the relative
effects on GI toxicity, and whether the cardioprotective effects of
aspirin persist during coprescription of other COX-inhibitors. It does
seem that the combination of sCOX-2 plus aspirin is indeed less GI toxic
than nsNSAID plus aspirin [Laine et al. 2007; Goldstein et al. 2006, 2007].
The beneficial cardiovascular effects of aspirin have been found to
persist in conjunction with both sCOX-2s and nsNSAIDs, including
celecoxib, rofecoxib, indomethacin and meloxicam but not ibuprofen [Strand, 2007].
It may be necessary to consider each drug individually rather than as a
class, as effects may not merely be mediated merely by COX inhibition
but involve pharmacokinetics, membrane binding and metabolism [Strand, 2007]. Although it may be too soon to change the overall suggestions outlined previously (Table 2),
if further studies are confirmatory, the combination of aspirin +
sCOX-2 + PPI may become the optimal treatment strategy for those with
cardiovascular disease and high risk of PUB.
questions on which clarity is needed to inform choices regarding the
clinical use of aspirin combined with NSAIDs concern the relative
effects on GI toxicity, and whether the cardioprotective effects of
aspirin persist during coprescription of other COX-inhibitors. It does
seem that the combination of sCOX-2 plus aspirin is indeed less GI toxic
than nsNSAID plus aspirin [Laine et al. 2007; Goldstein et al. 2006, 2007].
The beneficial cardiovascular effects of aspirin have been found to
persist in conjunction with both sCOX-2s and nsNSAIDs, including
celecoxib, rofecoxib, indomethacin and meloxicam but not ibuprofen [Strand, 2007].
It may be necessary to consider each drug individually rather than as a
class, as effects may not merely be mediated merely by COX inhibition
but involve pharmacokinetics, membrane binding and metabolism [Strand, 2007]. Although it may be too soon to change the overall suggestions outlined previously (Table 2),
if further studies are confirmatory, the combination of aspirin +
sCOX-2 + PPI may become the optimal treatment strategy for those with
cardiovascular disease and high risk of PUB.
Upper GI bleeding with antiplatelet agents
Three
classes of antiplatelet agent are in common use: aspirin, dipyridamole
and the P2Y12 (ADP-) receptor antagonists exemplified by clopidogrel. Of
these, dipyridamole does not seem to be associated with increased risk
of AUGIB [Ibanez et al. 2006] and, as it is only generally used in combination with aspirin, management decisions are based on the aspirin risk.
classes of antiplatelet agent are in common use: aspirin, dipyridamole
and the P2Y12 (ADP-) receptor antagonists exemplified by clopidogrel. Of
these, dipyridamole does not seem to be associated with increased risk
of AUGIB [Ibanez et al. 2006] and, as it is only generally used in combination with aspirin, management decisions are based on the aspirin risk.
Aspirin
and clopidogrel inhibit platelet function by separate and complimentary
mechanisms, and both are associated with increased risk of AUGIB; the
mechanism probably stems from impaired platelet aggregation enhancing
bleeding from pre-existing gastric erosions [Abraham et al. 2010].
There are data showing that platelet derived factors influence peptic
ulcer healing and vascularity and inhibition of this facet of platelet
function probably also contributes [Ma et al. 2001].
Enteric coated or buffered aspirin preparations do not provide
significant protection, suggesting that systemic rather than local
effects are most important [Bhatt et al. 2008].
Although the COX-1 inhibitory effect of aspirin on the GI mucosa might
be expected to cause greater rates of PUB, in practice clopidogrel is
not clinically safer from this perspective. Although rates of both total
GI haemorrhage (1.99% versus 2.66%) and life-threatening GI
haemorrhage in the CAPRIE trial were statistically lower in clopidogrel
compared with aspirin-treated patients, the difference in rate of major
bleeding of 2/1000 per year is not meaningful in determining
preventative strategies (CAPRIE Steering Committee, 1996).
Similar results have been seen in a large population-based case control
study where clopidogrel was associated with the same degree of
increased risk as aspirin, anticoagulants or nsNSAIDs (relative risk
compared with no treatment of 1.9–4.2) [Lanas et al. 2006].
Dual antiplatelet combination is associated with increased risk of PUB.
Overall rates of GI bleeding are about 0.6–1.0% per year with aspirin
alone and are increased by about approximately a further 1% by the
addition of clopidogrel [Lanas et al. 2006; Ng et al. 2008; Hsu et al. 2011; CAPRIE Steering Committee, 1996; Lin et al. 2011].
There are less data for other P2Y12 antagonists such as prasugrel or
ticagrelor, but given the similar mechanism of action, similar effects
are likely. Compared with NSAIDs, the risk factors for bleeding with
antiplatelets are less well defined but in practice a similar risk
stratification strategy as outlined for NSAIDs in Box 1
is appropriate. It is important to continue cardioprotective aspirin
after a PUB in patients with established cardiovascular disease as
discontinuation has been reported to be associated with a high rate of
death or cardiovascular events in the 6 months after aspirin cessation
(31% compared with 8% in those that had aspirin re-introduced) [Derogar et al. 2013].
A combined aspirin cardiovascular/GI risk calculator has recently been
published based on similar risk assumptions, and although this requires
further external validation, this can be used to guide physicians in
making decisions about the appropriateness of both aspirin and
gastroprotection in various circumstances [Lanas et al. 2013].
and clopidogrel inhibit platelet function by separate and complimentary
mechanisms, and both are associated with increased risk of AUGIB; the
mechanism probably stems from impaired platelet aggregation enhancing
bleeding from pre-existing gastric erosions [Abraham et al. 2010].
There are data showing that platelet derived factors influence peptic
ulcer healing and vascularity and inhibition of this facet of platelet
function probably also contributes [Ma et al. 2001].
Enteric coated or buffered aspirin preparations do not provide
significant protection, suggesting that systemic rather than local
effects are most important [Bhatt et al. 2008].
Although the COX-1 inhibitory effect of aspirin on the GI mucosa might
be expected to cause greater rates of PUB, in practice clopidogrel is
not clinically safer from this perspective. Although rates of both total
GI haemorrhage (1.99% versus 2.66%) and life-threatening GI
haemorrhage in the CAPRIE trial were statistically lower in clopidogrel
compared with aspirin-treated patients, the difference in rate of major
bleeding of 2/1000 per year is not meaningful in determining
preventative strategies (CAPRIE Steering Committee, 1996).
Similar results have been seen in a large population-based case control
study where clopidogrel was associated with the same degree of
increased risk as aspirin, anticoagulants or nsNSAIDs (relative risk
compared with no treatment of 1.9–4.2) [Lanas et al. 2006].
Dual antiplatelet combination is associated with increased risk of PUB.
Overall rates of GI bleeding are about 0.6–1.0% per year with aspirin
alone and are increased by about approximately a further 1% by the
addition of clopidogrel [Lanas et al. 2006; Ng et al. 2008; Hsu et al. 2011; CAPRIE Steering Committee, 1996; Lin et al. 2011].
There are less data for other P2Y12 antagonists such as prasugrel or
ticagrelor, but given the similar mechanism of action, similar effects
are likely. Compared with NSAIDs, the risk factors for bleeding with
antiplatelets are less well defined but in practice a similar risk
stratification strategy as outlined for NSAIDs in Box 1
is appropriate. It is important to continue cardioprotective aspirin
after a PUB in patients with established cardiovascular disease as
discontinuation has been reported to be associated with a high rate of
death or cardiovascular events in the 6 months after aspirin cessation
(31% compared with 8% in those that had aspirin re-introduced) [Derogar et al. 2013].
A combined aspirin cardiovascular/GI risk calculator has recently been
published based on similar risk assumptions, and although this requires
further external validation, this can be used to guide physicians in
making decisions about the appropriateness of both aspirin and
gastroprotection in various circumstances [Lanas et al. 2013].
As
the absolute risk of bleeding with a single antiplatelet agent is low,
gastroprotection is not usually recommended in the absence of other risk
factors [Abraham et al. 2010].
Therefore prevention is usually recommended for the over 65s, when
combined with other drugs increasing the risk (including another
nondipyidamole antiplatelet) or a past history of dyspepsia, peptic
ulcer or bleeding.
the absolute risk of bleeding with a single antiplatelet agent is low,
gastroprotection is not usually recommended in the absence of other risk
factors [Abraham et al. 2010].
Therefore prevention is usually recommended for the over 65s, when
combined with other drugs increasing the risk (including another
nondipyidamole antiplatelet) or a past history of dyspepsia, peptic
ulcer or bleeding.
Coprescription of a PPI with antiplatelet therapy is usually recommended if gastroprotection is indicated [Abraham et al. 2010]. High-dose famotidine has also been showed to be effective against aspirin-induced ulceration [Taha et al. 2009], but in another randomized trial, pantoprazole was superior to famotidine in prevention of PUB [Ng et al. 2010] and case-control studies support the concept that PPI coprescription is more effective than H2RAs [Lanas et al. 2007b].
H2RAs have not been specifically examined in randomized trials in
relation to clopidogrel-induced AUGIB, although the American College of
Cardiology Foundation (ACCF), American College of Gastroenterology and
American Heart Association (AHA) consensus guideline suggests that H2RA
(but not cimetidine) may be an option for clopidogrel-treated patients
with modestly increased bleeding risk [Abraham et al. 2010].
In a randomized placebo-controlled trial, after an aspirin-induced but
not necessarily complicated, peptic ulcer clopidogrel alone was
associated with an ulcer recurrence rate of 11% at 6 months and
esomprazole reduced this to 1.2% [Hsu et al. 2011]
and in a similar randomized trial after aspirin-induced bleeding ulcer,
clopidogrel (13.6% recurrent ulcer complications) was inferior to
esomeprazole plus aspirin (0%) [Lai et al. 2006].
When looking specifically at ulcer bleeding, in a randomized trial
omeprazole reduced upper GI bleeding induced by the aspirin–clopidogrel
combination by 87% compared with placebo [Bhatt et al. 2010]. There are no studies comparing aspirin plus PPI against clopidogrel plus PPI in the secondary prevention of PUB.
H2RAs have not been specifically examined in randomized trials in
relation to clopidogrel-induced AUGIB, although the American College of
Cardiology Foundation (ACCF), American College of Gastroenterology and
American Heart Association (AHA) consensus guideline suggests that H2RA
(but not cimetidine) may be an option for clopidogrel-treated patients
with modestly increased bleeding risk [Abraham et al. 2010].
In a randomized placebo-controlled trial, after an aspirin-induced but
not necessarily complicated, peptic ulcer clopidogrel alone was
associated with an ulcer recurrence rate of 11% at 6 months and
esomprazole reduced this to 1.2% [Hsu et al. 2011]
and in a similar randomized trial after aspirin-induced bleeding ulcer,
clopidogrel (13.6% recurrent ulcer complications) was inferior to
esomeprazole plus aspirin (0%) [Lai et al. 2006].
When looking specifically at ulcer bleeding, in a randomized trial
omeprazole reduced upper GI bleeding induced by the aspirin–clopidogrel
combination by 87% compared with placebo [Bhatt et al. 2010]. There are no studies comparing aspirin plus PPI against clopidogrel plus PPI in the secondary prevention of PUB.
Therefore PPI therapy reduces bleeding associated with antiplatelet drugs [Bhatt et al. 2010],
but recent studies have questioned whether the combination of PPI and
clopidogrel is appropriate. Clopidogrel is a prodrug, which requires
biotransformation by the hepatic cytochrome enzyme, CYP2C19, for
activity. Certain drugs, including some PPIs, inhibit this enzyme and
pharmacodynamic studies have clearly shown that co-administration of
PPIs with clopidogrel appeared to impair the antiplatelet action of
clopidogrel [Gilard et al. 2008].
Initial results from observational studies seemed to indicate that the
addition of a PPI was associated with an increased cardiovascular risk
in clopidogrel-treated patients. The current guidance from the United
Kingdom Medicine and Healthcare Products Regulatory Agency (MHRA) and
the United States Federal Drug Administration (FDA) continue to suggest
avoiding the addition of omeprazole [FDA 2010] or either omeprazole or esomeprazole [MHRA 2010] to clopidogrel (because these may be associated with greater CYP2C19 inhibition) [MHRA, 2010].
Subsequent studies and meta-analyses have shown that there does not
seem to be a clinically significant interaction between PPIs and
clopidogrel [Mizia-Stec et al. 2012; Focks et al. 2013; Kwok and Loke, 2010]
and certainly in the highest GI bleeding risk patients the addition of
PPI gastroprotection would be appropriate. Although there are limited
data in this situation, theoretically pantoprazole would be expected to
have the least interaction with clopidogrel [Mizia-Stec et al. 2012].
but recent studies have questioned whether the combination of PPI and
clopidogrel is appropriate. Clopidogrel is a prodrug, which requires
biotransformation by the hepatic cytochrome enzyme, CYP2C19, for
activity. Certain drugs, including some PPIs, inhibit this enzyme and
pharmacodynamic studies have clearly shown that co-administration of
PPIs with clopidogrel appeared to impair the antiplatelet action of
clopidogrel [Gilard et al. 2008].
Initial results from observational studies seemed to indicate that the
addition of a PPI was associated with an increased cardiovascular risk
in clopidogrel-treated patients. The current guidance from the United
Kingdom Medicine and Healthcare Products Regulatory Agency (MHRA) and
the United States Federal Drug Administration (FDA) continue to suggest
avoiding the addition of omeprazole [FDA 2010] or either omeprazole or esomeprazole [MHRA 2010] to clopidogrel (because these may be associated with greater CYP2C19 inhibition) [MHRA, 2010].
Subsequent studies and meta-analyses have shown that there does not
seem to be a clinically significant interaction between PPIs and
clopidogrel [Mizia-Stec et al. 2012; Focks et al. 2013; Kwok and Loke, 2010]
and certainly in the highest GI bleeding risk patients the addition of
PPI gastroprotection would be appropriate. Although there are limited
data in this situation, theoretically pantoprazole would be expected to
have the least interaction with clopidogrel [Mizia-Stec et al. 2012].
H. pylori, aspirin and NSAID negative ulcers
Peptic
ulceration in the absence of the traditional major risk factors is
increasing recognized as a significant clinical problem. It is important
to consider gastrinoma as a cause of such ulcers, but in practice, this
is a rare cause. These idiopathic ulcers are associated with an overall
poor prognosis, with a very high incidence of adverse cardiovascular
outcomes but also a very high risk of rebleeding (42% at 7 years) [Wong et al. 2009].
Continued acid suppression would be recommended as secondary prevention
following an AUGIB from an idiopathic ulcer. However, this may not be
that effective. Wong and colleagues reported that the continued use of a
PPI was not associated with a significantly reduced risk of rebleeding
(relative risk 0.7, 95% confidence interval 0.4–1.1) [Wong et al. 2012].
It may yet be proved that mucosal protectants such as misoprostol or
sucralfate offer an advantage, but at present it still seems sensible to
recommend PPI gastroprotection in this group.
ulceration in the absence of the traditional major risk factors is
increasing recognized as a significant clinical problem. It is important
to consider gastrinoma as a cause of such ulcers, but in practice, this
is a rare cause. These idiopathic ulcers are associated with an overall
poor prognosis, with a very high incidence of adverse cardiovascular
outcomes but also a very high risk of rebleeding (42% at 7 years) [Wong et al. 2009].
Continued acid suppression would be recommended as secondary prevention
following an AUGIB from an idiopathic ulcer. However, this may not be
that effective. Wong and colleagues reported that the continued use of a
PPI was not associated with a significantly reduced risk of rebleeding
(relative risk 0.7, 95% confidence interval 0.4–1.1) [Wong et al. 2012].
It may yet be proved that mucosal protectants such as misoprostol or
sucralfate offer an advantage, but at present it still seems sensible to
recommend PPI gastroprotection in this group.
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