Overprescribing proton pump inhibitors
BMJ 2008; 336 doi: https://doi.org/10.1136/bmj.39406.449456.BE (Published 03 January 2008) Cite this as: BMJ 2008;336:2
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From the perspective of Patient & Public Involvement (PPI)might
Proton Pump Inhibitor (PPI)prescribing be a case of "waste not, want not"?
Competing interests:
Member of West Sussex PPI Forum
Competing interests: No competing interests
Dear Sir,
We read with interest your article on the over prescribing of proton
pump inhibitors(PPIs) (1). The authors explain the economic implications
associated with over prescription of PPIs and possible adverse events
which stem from this. One such possible side effect associated with PPIs,
which has come to light in the recent years, is increased fracture risk
secondary to accelerated osteoporosis (2).
Osteoporosis is defined as a reduction in bone mass and disruption of
bone architecture, resulting in reduced bone strength and increased
fracture risk. Hip fracture is one of the significant presentations of
osteoporosis. The mortality rate during the first year after a hip
fracture is estimated to be around 20% (3). Hip fractures have big
socioeconomic implications incurring huge health care costs due to
inevitable hospitalisation, surgery and rehabilitation. One year following
a hip fracture, it has been found that 40% of patients are unable to walk
independently, 60% cannot carry out at least one activity of daily living,
and 80% or more are unable to carry out at least one independent activity
of daily living, such as shopping, or driving (4).
An acidic environment in the gastrointestinal tract facilitates the
release of ionised calcium from insoluble calcium salts, such as, calcium
carbonate (5). Proton pump inhibitors by reducing gastric acidity
interferes with calcium absorption . In a case control study by Yang et
al in 2006, they found that long-term PPI therapy, particularly at high
doses, is associated with increased risk of hip fracture. The adjusted
odds ratio for hip fracture associated with more that 1 year of PPI
therapy was 1.44 (95% confidence interval) (2).
Dyspepsia and regurgitation are common side effects encountered with
bisphosphonates which is the first line treatment for osteoporosis. de
Vries et al, in 2007, conducted a retrospective cohort study using the
General Practice Research Database and found that there was an increased
risk of hip fractures in patients taking concomitant bisphosphonates and
PPIs (6). They suggest that acid-suppressant medications may attenuate the
protective effects of bisphosphonates on fracture risk.
We agree that a judicious evidence based use of proton pump
inhibitors is warranted and prescriptions should be reviewed on a
regularly. Over prescribing PPIs is not only associated with economic
implications but also significant mortality.
References
1.Forgacs I, Loganayagam A. Overprescribing proton pump inhibitors.
Bmj 2008;336(7634):2-3.
2.Yang YX, Lewis JD, Epstein S, Metz DC. Long-term proton pump
inhibitor therapy and risk of hip fracture. Jama 2006;296(24):2947-53.
3. Rowe R. Comment: preventive strategies: is current clinical
practice effective for bones? Br J Clin Pract 1996;50(1):47-9.
4.Cooper C. The crippling consequences of fractures and their impact
on quality of life. Am J Med 1997;103(2A):12S-17S; discussion 17S-19S.
5. Sheikh MS, Santa Ana CA, Nicar MJ, Schiller LR, Fordtran JS.
Gastrointestinal absorption of calcium from milk and calcium salts. N Engl
J Med 1987;317(9):532-6.
6. de Vries F, Cooper AL, Logan RF, Cockle SM, van Staa TP, Cooper C.
Fracture risk in patients receiving concomitant bisphosphonate and acid-
suppressive medication or bisphosphonates alone. Osteoporosis Int
2007;18(Suppl 3):S261.
Competing interests:
None declared
Competing interests: No competing interests
Is this article inspired by one of Mr Brown’s spin “doctors”? It
contains some incredible errors:
1. “The first generic proton pump inhibitor (omeprazole) was
introduced in 2002.” Wrong! Omeprazole has been in widespread use since
the 1980s. The fact that a serious side-effect profile has not emerged is
very reassuring.
2. “Effective and less expensive alternative drugs, such as H2 receptor
antagonists are available for many patients.” Wrong! They are less
effective and more expensive, as detailed by the responses above.
Watch for bias:
1. The repeated use of “over-prescribing” and “over-use” descriptions
are like they are proven. The lay media pick up on this. I disagree.
2. Incredibly there is no mention of patients’ use of these drugs as a
lifestyle additive, to allow them to drink alcohol and eat curries. I see
this all the time
3. Why not also mention that omeprazole has been available without
prescription since 2004, a sure marker of safety?
Instead of political campaigns against doctors, why not take action?
If money is the real underlying issue, make patients pay for it by central
regulation. Failing that political decision, I am happy to continue to
prescribe this wonder drug liberally for my patients…
Competing interests:
None declared
Competing interests: No competing interests
Awareness of potentially lethal side effects of omeprazole, such as
increased predisposition to clostridium difficile infection, would justify
a resurgence of interest in the use of misoprostol for prophylaxis against
aspirin-related peptic ulceration. Misoprostol 200 mcg qds is just as
effective as lansaprazole 15-30 mg/d in preventing gastric ulceration in
long-term users of non steriodal anti inflammators drugs(NSAID's)(1), of
which aspirin is an example. The incidence of misoprostol-related
gastrointestinal side effects, such as abdominal cramps and diahrroea, can
be reduced by halving the dose to 200 mcg bd. At that dose prophylactic
efficacy is not as good as with the 200 mcg qds dose.
Nevertheless, the
incidence of NSAID-related gastric ulceration is significantly(p=0.02)
lower in patients receiving misoprostol 200 mcg bd than in the placebo
group. Likewise the incidence of duodenal ulceration is
significantly(p=0.04) lower in patients receiveing misoprostol 200 mcg bd
than in the placebo group(2). More recent anxieties relate to the
possibility of attenuation of the antiplatelet action of clopidogrel
during combined therapy with aspirin when omeprazole is co-prescribed to
prevent peptic ulceration. What has been found is that omeprazole
significantly(p <0.0001) decreased clopidogrel inhibitory effect on
P2Y12(3), the ADP activated receptor which plays a central role in
platelet activation(4), and is the target of P2Y12 receptor antagonists
such as clopidogrel(5)
References
(1) Graham D., Agrawal NM., Campbell DR et al
Ulcer prevention in long-term users of non-steriodal anti-inflammatory
drugs
Archives of Internal Medicine 2002:162:169075
(2) Raskin JB., White RH., Jackson JE et al
Misoprostol dosage in the prevention of non-steriodal anti-inflammatory
drug-induced gastric and duodenal ulcers: a comparison of three regimens
Annals of Internal Medicine 1995:123:344-50
(3) Gilard M., Arnaud B., Cornily J-C et al
Influence of omeprazole on the antiplatelet action of clopidogrel
associated with aspirin
Journal of the American College of Cardiology 2008:51:256-60
(4) Dorsam RT., Kunapuli SP
Central role of the P2Y12 receptor in platelete function
Journal of Clinical Investigation 2004:113:340-5
(5) Malinin A., Pokov A., Sperling M et al
Monitoring platelet inhibition after clopidogrel with the VerifyNow-
P2Y12(r) rapid analyser: The VERIfy Thrombosis risk ASsessment(VERITAS)
study
Thrombosis Research 2007:119:277-84
Competing interests:
None declared
Competing interests: No competing interests
Editor, I read with interest the article on overprescribing of PPIs.
It is common practice for juniors to co-prescribe PPIs for patients who
are being commenced on aspirin therapy as primary or secondary prevention
for cardiovascular disease. Especially amongst juniors this is fuelled by
a desire to prevent upper GI bleeds but is often not evidence based.
A web based search brought me to the NHS Primary Care Answering
Scheme web site www.clinicalanswers.nhs.uk where the question of
appropriate prescribing of PPIs in conjunction with aspirin therapy is
discussed.
They suggest using PPI's in conjunction with aspirin for "people at
high risk of GI adverse effects or who continue to have dyspepsia", or
alternatively using clopidogrel. They go on to quote from a study on
NSAIDs that patients with one or more risk factors of; age over 65 years,
previous history, comorbidity, prolonged use, high doses, and other drugs,
like aspirin or anticoagulants: gastroprotection, principally a PPI is
indicated. (Bandolier. Gastroprotection with NSAID: do we follow
guidelines? 2007)
In an effort to reduce some of the excessive prescription of PPIs it
might be helpful to include this in local hospital guidelines especially
for junior staff and pharmacists.
Competing interests:
None declared
Competing interests: No competing interests
The excessive use of PPI drugs is not limited to the UK. In New
Zealand I have noted an association between polypharmacy and the use of
PPI. In such cases I have been known to jokingly suggest to patients that
their PPI is for treating the indigestion caused by their "drug salad."
Dr J Welch
GP
Marlborough,
New Zealand
Competing interests:
None declared
Competing interests: No competing interests
Forgacs and Loganayagam (1) have written a thorough and measured
summary of the economic costs of unnecessary PPI use. However, the wasted
NHS resource they describe pales into insignificance beside the hundreds
of extra deaths from C.difficile this may cause each year.
First described in 2003 (2), the positive association between PPI use
and C.difficile has now been confirmed in numerous studies worldwide, a
systematic review (3), and recently an animal model (4). In 1999, there
were about 10 million community PPI prescriptions in England & Wales,
and less than 20,000 reported cases of C.difficile. By 2006 there were
about 25 million PPI prescriptions, and 55,000 cases of C.difficile.
Antibiotic prescriptions actually fell over this period, and contrary to
the popular press, hospitals are cleaner now than they have been for many
years.
There is no longer any doubt that PPIs and Cdifficile are associated.
If this is a causal association, overuse of these drugs may be causing
many thousands of additional cases, and hundreds of deaths in the UK each
year. PPIs are highly effective when used appropriately, but this does not
excuse ignoring NICE guidance and a potentially lethal adverse effect.
1) Forgacs I, Loganayagam A. Over prescribing proton pump inhibitors.
BMJ 2008; 336(7634):2-3
2) Cunningham R, Dale B, Undy B, Gaunt PNG. Proton pump inhibitors as
a risk factor for Clostridium difficile diarrhoea. Journal of Hospital
Infection 2003;54:243-245.
3) Leonard J, Marshall JK, Moayyedi P. Systematic review of the risk
of enteric infection in patients taking acid suppression. Am J
Gastroenterol 2007;102:1-10.
4) Kaur S, Vaishnavi C, Prasad K, Ray P, Kochhar R. Comparative role
of antibiotic and proton pump inhibitor in experimental Clostridium
difficle infection in mice. Microbiol. Immunol. 2007;51(12):1209-1214
Competing interests:
None declared
Competing interests: No competing interests
Dear Editor,
Forgacs & Loganayagam discuss the over prescribing of proton pump
inhibitors (PPI) in clinical practice (1). However, we would like to point
out that PPIs are not a recognised cause of osteoporosis, as stated in
this editorial. The cited article by Yang et al.(2) found that chronic use
of proton pump inhibitors (PPI) was associated with increased risk of hip
fracture, consistent with other studies linking their use to increased
fracture risk (3,4,5).
This association is particularly relevant to the management of
osteoporosis as bisphosphonates, the most common group of medications
prescribed for patients with osteoporosis, are associated with upper
gastro-intestinal effects, such as dyspepsia (6,7), which may lead to
additional prescribing of PPIs (8). Therefore, minimising the use of PPIs
should also be an important consideration in the management of
osteoporotic patients.
Yours faithfully,
Dr Alun Cooper
REFERENCES
1.Forgacs I, Loganayagam A. Overprescribing of proton pump
inhibitors. BMJ 2008; 336:2-3. (5 January).
2.Yang Y-X, Lewis JD, Epstein S, Metz DC. Long-term proton pump inhibitor
therapy and risk of hip fracture. JAMA 2006; 296 (24), 2947-2953.
3.Vestergaard P, Rejnmark L, Mosekilde L. Proton pump inhibitors,
histamine H2 receptor antagonists, and other antacid medication and the
risk of fracture. Calcif Tissue Int. 2006; 79, 76-83.
4.Yu E W, Shinoff C, Blackwell T, Ensrud K, Hillier T, Bauer D C. Use of
acid-suppressive medications and risk of bone loss and fracture in
postmenopausal women. J Bone Min Res 2006; 21 (Suppl. 1), S281.
5.De Vries F, Cooper AL, Logan RF, Cockle SM, van Staa TP, Cooper C.
Fracture risk in patients receiving concomitant bisphosphonate and acid-
suppressive medication or bisphosphonates alone. Osteoporosis Int. 2007;
18(Suppl 3):S261.
6.Barrera BA, Wilton LV, Harris S, Shakir SAW. Prescription-event
monitoring study on 13,164 patients prescribed risedronate in primary care
in England. Osteoporos Int. 2005; 16, 1989-1998.
7.Biswas PN, Wilton LV, Shakir SAW. Pharmacovigilance study of alendronate
in England. Osteoporos Int. 2003; 14, 507-514.
8.Roughead EE, McGeechan K, Sayer GP. Bisphosphonate use and subsequent
prescription of acid suppressants. Br J Clin Pharm. 2004; 57(6), 813-816.
Competing interests:
None declared
Competing interests: No competing interests
The rapid responses have been very interesting.... BUT they seem to
be missing the real problem:
When prednisone/steroids became available they were expensive, but
had magnificent benefits then they got cheaper and massively overused and
the horrific side effects were noticed! Then a rational restricted use
protocol was developed..
When barbiturates were first available they were expensive and when
they became cheaper and abused they were related to nasty side
effects,(addiction, overdose etc) and a rational restricted use protocol
was developed and now:-
The NSAIDs followed the same pattern and now have a rational and
restricted use protocol.
PPI's have become cheap and massively prescribed...
BUT... everyone is missing the major and most important point... just as
excess use and abuse of steroids/ barbiturates & NSAIDS caused massive
long term side effects:- SO DO PPIs to whole body function!
Bearing in mind the gasto-intestinal specialists' 'apparant
ignorance' of the long term side effects to all gut areas & whole
body, it is time to develop a rational restricted use protocol (high
initial dose BD, to once daily to alternate daily at weekly intervals),and
using simpler and cheaper but less harmful antacids and the histamine H2
receotor agonists in the interim periods, at the Family Physician/GP
level.
What are the massive costs of the indicated side effects of these
drugs causing already...yet alone over longer terms?
No one knows!!!
There are only three listed long term review studies on PPIs, two
based on cost (1,2) and one on age (3).. none on dysautonomic or other
side effects to the whole gut system as indicated in my 2002 letter.
So why has there been no research on those oesophagus, stomach and
whole of gut problems, so often encountered in Family Medicine/General
Practice?
The most frequent specialist advice to my patients have received has
been to increase the dose!!!
"First do no harm"? Forgotten or just ignored?
I am becoming older, wiser and more cynical of specialist limited advice
as my experience grows...(now >47 years!!)
References:
1: O'Connor JB, Provenzale D, Brazer S.
Economic considerations in the treatment of gastroesophageal reflux
disease: a review.
Am J Gastroenterol. 2000 Dec;95(12):3356-64. Review.
PMID: 11151862 [PubMed - indexed for MEDLINE]
2: Goeree R, O'Brien B, Hunt R, Blackhouse G, Willan A, Watson J.
Economic evaluation of long-term management strategies for erosive
oesophagitis.
Pharmacoeconomics. 1999 Dec;16(6):679-97.
PMID: 10724795 [PubMed - indexed for MEDLINE]
3: Lazzaroni M, Bianchi Porro G.
Treatment of peptic ulcer in the elderly. Proton pump inhibitors and
histamine H2 receptor antagonists.
Drugs Aging. 1996 Oct;9(4):251-61. Review.
PMID: 8894523 [PubMed - indexed for MEDLINE]
Competing interests:
None declared
Competing interests: No competing interests
Re: Overprescribing proton pump inhibitors
PPIs increase mortality.
Patients might reject most prescriptions, if ethically presented with this new evidence.
References
http://bmjopen.bmj.com/content/7/6/e015735
http://gut.bmj.com/content/early/2017/09/18/gutjnl-2017-314605
https://www.ncbi.nlm.nih.gov/pubmed/29233498
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4973085/
Competing interests: No competing interests