Combining aspirin with antithrombotic agents
BMJ 2006; 333 doi: https://doi.org/10.1136/bmj.38992.480544.80 (Published 05 October 2006) Cite this as: BMJ 2006;333:712
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Professor Sung has rightly pointed out the risk of gastrointestinal
bleed and the need to balance between cerebrovascular or cardiovascular
protection versus risk of GI bleed(1).An important factor contributing to
this is the duration of therapy.The NICE assessment report on the clinical
and cost effectiveness of clopidogrel in combination with aspirin versus
aspirin alone in the treatment of NonSTelevation Acute Coronary Syndromes
clearly sates that substantial part of the benefit derived from
clopidogrel is achieved by three months,with a further small benefit over
the remaining nine months(2).This is demonstrated by the CURE study as
well(3).In real clinical practice,elderly patients who are on aspirin and
clopidogrel combination for years and who are on triple therapy with
aspirin,clopidogrel and warfarin presenting with a drop in haemoglobin
values are not so uncommon.This made me do an audit of 50 patients who had
a NonSTelevation ACS in the past,12 of them were on aspirin and
clopidogrel for more than 12 months.
The cost effectiveness should also be taken into consideration.Even
though treatment with clopidogrel for twelve months remained cost
effective,provisional findings indicate that shorter traetment duartions
of three months may be cost effective in low risk patients(2).
References
1.Combining Aspirin with Antithrombotic Agents,BMJ2006;333:712-713
2.NICE assessment report:A rapid and systematic review of the clinical and
cost effectiveness of clopidogrel used in combination with aspirin
compared to aspirin alone in the treatment of Non Stelevation ACS;23 March
2004
3.The Clopidogrel in Unstable Angina to prevent Recurrent Events,New
England Journal of Medicine2001;345:494-502.
Competing interests:
None declared
Competing interests: No competing interests
Sung[1] comments on the bleeding risks associated with anti-platelets
agents, either alone or in combination, and possible strategies for risk
reduction. Although glycoprotein (GP) IIb/IIIa antagonists were not
discussed, their use in cardiology patients, in combination with aspirin,
clopidogrel and heparin, has increased markedly in the acute setting,
particularly in those receiving percutaneous coronary intervention (PCI).
Adjusted registry data suggests that they increase the risk of bleeding at
least twofold in these patients, particularly when combined with
heparin.[2]
Both heparin and GP IIb/IIIa antagonists can cause thrombocytopaenia
and increase the risk of mucosal, gastrointestinal and intracranial
bleeding. The reported incidence of GP IIb/IIIa antagonist-induced
thrombocytopaenia varies depending on the agent and platelet definition
used. However, its presence is associated with an increase in severe
bleeding, a higher risk of recurrent myocardial infarction, a greater
transfusion requirement, and an increased 30-day[3] and one-year risk of
death.[4]
There are some data that suggest statins may reduce the risk of
gastrointestinal bleeding in all groups of patients presenting as an acute
coronary syndrome (ACS), including those taking GP IIb/IIIa
antagonists.[5] It is thought they increase the systemic production of
protective prostaglandins that may protect the gastric mucosa and prevent
gastrointestinal bleeding.[5]
[1] Sung JJY. Combining aspirin with antithrombotic agents. BMJ
2006;333:712-713.
[2] Horwitz PA, Berlin JA, Sauer WH, Laskey WK, Krone RJ, Kimmel SE.
Bleeding risk of platelet glycoprotein IIb/IIIa receptor antagonists in
broad-based practice (results from the Society for Cardiac Angiography and
Interventions Registry). Am J Cardiol 2003;91:803-6.
[3] Merlini PA, Rossi M, Menozzi A, Buratti S, Brennan DM, Moliterno
DJ, Topol EJ, Ardissino D. Thrombocytopenia caused by abciximab or
tirofiban and its association with clinical outcome in patients undergoing
coronary stenting. Circulation 2004;109:2203-6.
[4] Scirica BM, Cannon CP, Cooper R, Aster RH, Brassard J, McCabe CH,
Charlesworth A, Skene AM, Braunwald E. Drug-induced thrombocytopenia and
thrombosis: Evidence from patients receiving an oral glycoprotein IIb/IIIa
inhibitor in the Orbofiban in Patients with Unstable coronary Syndromes-
(OPUS-TIMI 16) trial. J Thromb Thrombolysis 2006;22:95-102.
[5] Atar S, Cannon CP, Murphy SA, Rosanio S, Uretsky BF, Birnbaum Y.
Statins are associated with lower risk of gastrointestinal bleeding in
patients with unstable coronary syndromes: analysis of the Orbofiban in
Patients with Unstable coronary Syndromes-Thrombolysis In Myocardial
Infarction 16 (OPUS-TIMI 16) trial. Am Heart J 2006;151:976.e1-6.
Competing interests:
None declared
Competing interests: No competing interests
Professor Sung states that the recommended strategy to prevent upper
gastrointestinal bleeding in patients on one or two antiplatelet agents is
open to debate, though the use of Proton Pump Inhibitors is
recommended.There is NICE guidance on the use of PPIs in this
situation.(1)
I have performed five groups of audits of fifty deceased patient
records in the last three years, using some of the "trigger tools" of the
Institute for Healthcare Improvement. This includes identifying those who
have had Clostridium difficile infection.
In the last audit where the average age at death was just over 80
years of age, 20 of the patients were on PPIs, 16 patients were on aspirin
alone, one on asasantin, and 3 were on aspirin with clopidogrel. Five
patients had C.diff in the days before they died, and 2 others had had
C.diff on previous admissions. Four of the patients with current C.diff
were also taking PPIs during their last admission.
A study is needed to monitor C.diff occurence in the group on aspirin
alone, and those on clopidogrel, aspirin and a PPI. PPIs will lessen the
hydrogen ion concentration in the stomach about 1000-fold throughout the
24 hour period. PPIs are thought to increase C.diff occurence 2-3 fold.(2,
3) H2 blockers are not thought to increase C.diff to this significant
extent.
1. National Institute for Clinical Excellence. Technology Appraisal
Guidance- No.7. Guidance on the use of Proton Pump Inhibitors in the
Treatment of Dyspepsia, July 2000.
2. Proton Pump Inhibitors as a risk factor for Clostridium difficile
diarrhoea. R. Cunningham, B. Dale, B. Undy, N. Gaunt. Journal of Hospital
Infection (2003) 54, 243-245.
3. Risk of Clostridium difficile diarrhoea among hospital inpatients
prescribed proton pump inhibitors: cohort and case-control studies. S.
Dial, K. Alrasadi, C. Manoukian, A Huang, R. Menzies. Canadian Medical
Association Journal. July 6, 2004; 171, 33-38.
Competing interests:
None declared
Competing interests: No competing interests
Recommended strategy to prevent upper gastrointestinal bleeding from antiplatelet agents
I read with interest the recent editorial by Professor Sung in the
October 7 issue of the Journal. (1) Although he clearly stated that most
of the recommendations in the Table were not evidence-based, I have
several concerns about the recommendations given.
Firstly, now that this
has been published in the Journal, I am afraid people will "forget" that
most of the recommendations are not evidence-based when they implement
them in practice (a type of so-called "reader bias" (2)). This will lead
to these recommendations becoming THE standard of practice, and this may
actually hinder the conduct of further studies.
Secondly, the author
states that age over 65 years is a risk factor for upper gastrointestinal
bleeding (UGIB) from low-dose aspirin. This is actually a controversial
issue. Several studies have concluded that age is not an independent risk
factor for UGIB with low-dose aspirin. (3-6) Lastly, there are no
references to support the classification of low risk, moderate risk and
high risk based on the number of risk factors present. As a specific
example, is the author suggesting that all patients with moderate risk
about to be started on low-dose aspirin alone be empirically treated with
an H. pylori eradication regimen before starting aspirin? I am unaware of
any studies to support such a suggestion. The studies that have assessed
H. pylori eradication in low-dose aspirin users have been for secondary
prevention (i.e., to prevent a recurrent bleed or ulcer), not for primary
prevention. (7,8) If we are to routinely test all moderate and high risk
patients for H. pylori before starting aspirin (either non-invasive tests
or endoscopic tests), the costs would be prohibitive. I would strongly
agree with Professor Sung that more studies are needed in this area - both
clinical trials and cost-effectiveness analyses - before his
recommendations are routinely implemented.
References
1. Sung JJY. Combining aspirin with antithrombotic agents. BMJ
2006;333:712-3.
2. Owen R. Reader bias. JAMA 1982;247:2533-4.
3. Ng W, Wong WM, Chen WH, et al. Incidence and predictors of upper
gastrointestinal bleeding in patients receiving low-dose aspirin for
secondary prevention of cardiovascular events in patients with coronary
artery disease. World J Gastroenterol 2006;12:2923-7.
4. Serrano P, Lanas A, Arroyo MT, Ferreira IJ. Risk of upper
gastrointestinal bleeding in patients taking low-dose aspirin for the
prevention of cardiovascular diseases. Aliment Pharmacol Ther 2002;16:1945
-53.
5. Lanas A, Fuentes J, Benito R, et al. Helicobacter pylori increases the
risk of upper gastrointestinal bleeding in patients taking low-dose
aspirin. Aliment Pharmacol Ther 2002;16:779-86.
6. Lanas A, Bajador, Serrano P, et al. Nitrovasodilators, low-dose
aspirin, other nonsteroidal anti-inflammatory drugs, and the risk of upper
gastrointestinal bleeding. N Engl J Med 2000;343:834-9.
7. Chan FKL, Chung SCS, Suen BY, et al. Preventing recurrent upper
gastrointestinal bleeding in patients with Helicobacter pylori infection
who are taking low-dose aspirin or naproxen. N Engl J Med 2001;344:967-73.
8. Lai KC, Lam SK, Chu KM, et al. Lansoprazole for the prevention of
recurrence of ulcer complications from long-term low-dose aspirin use. N
Engl J Med 2002;346:2033-8.
Competing interests:
None declared
Competing interests: No competing interests