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Study design
What were the key results?
What were the main limitations of this study?
Where does this study fit with current practice?
Should this study change practice?

The bottom line Combinations of aspirin plus clopidogrel and aspirin plus warfarin are associated with particularly high rates of serious upper gastrointestinal bleeding. These combinations should be used with care, as the risk of major bleeding may outweigh any benefits (e.g. reductions in cardiovascular events). Should this study change practice? This case-control study1 suggests that combinations of aspirin plus clopidogrel and aspirin plus warfarin should only be used with caution for conditions where it has been established that the benefits outweigh the increased risk of bleeding, and then only for a limited time. The risk of bleeding with aspirin plus dipyridamole appears lower. This supports national policies for the use of aspirin with clopidogrel or aspirin with modified-release dipyridamole.2,3 There are likely to be further indications for combination antithrombotic therapy when the final NICE guidance for the secondary prevention of myocardial infarction is published.4

Source
Hallas J, Dall M, Andries A, et al. Use of single and combined antithrombotic therapy and risk of serious upper gastrointestinal bleeding: population based case-control study. BMJ, doi:10.1136/bmj.38947.697558.AE (published 19th September 2006)

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Study design

This Danish population based case-control study¹ assessed the risk of serious upper gastrointestinal (GI) bleeding with antithrombotic agents, alone and in combination, and looked at trends in the use of antithrombotic drugs.

The discharge summaries of patients who were admitted to hospital between January 2000 and December 2004 with a main diagnosis of peptic ulcer or gastritis were reviewed. Cases were included in the study if they had significant bleeding (melaena, subnormal haemoglobin, transfusion) and a potential bleeding source in the stomach or duodenum identified on endoscopy or surgery. The investigators were blinded to the exposure of the subjects to antithrombotic agents. The 1443 cases identified were age- and sex-matched to 57,720 controls who had not been admitted for GI bleeding.

The main outcome measure was exposure to low-dose aspirin, clopidogrel, dipyridamole, vitamin K antagonists (e.g. warfarin) and combined antithrombotic treatment. Adjustments were made for potential confounders including current drug use (e.g. non-steroidal anti-inflammatory drugs [NSAIDs], selective serotonin reuptake inhibitors [SSRIs], anti-ulcer drugs), and past diagnoses (e.g. peptic ulcer, upper GI bleeding, diabetes, ischaemic heart disease).

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What were the key results?

Cases were more likely to have chronic diseases, or to take antithrombotic drugs, NSAIDs, SSRIs, or gastroprotective agents than controls. In all, 26.3% of cases were exposed to at least one antithrombotic drug, and 8.8% of cases died within 30 days of their admission date.

The odds of having a serious upper GI bleed were almost doubled when aspirin, warfarin and dipyridamole were taken alone (see Table). For clopidogrel alone, there was no significant increase in serious upper GI bleeding rates. However, the confidence interval (CI) around the adjusted odds ratio (OR) is wide relative to the other treatments, and the possibility of a similar increase in bleeding cannot be ruled out.

The adjusted OR for serious upper GI bleeding for someone taking combined antithrombotics was consistently higher than for the single drug regimens (see Table). The combination of aspirin and clopidogrel was associated with a seven-fold increase in the odds of bleeding compared with a five-fold increase for the combination of aspirin and warfarin. However, the true magnitude of the increased odds is uncertain as the number of patients taking a combination of drugs was small and the confidence intervals are wide.

The number of treatment years to produce one additional serious upper GI bleed was 124 for the combination of aspirin and clopidogrel, and 184 for aspirin and warfarin. The risk of combined therapy appears to be higher than a simple addition of the risks of the individual drugs. However, the increase in risk of serious upper GI bleeding seems much smaller for dipyridamole plus aspirin than for the other combinations.

During the four-year study period, use of combined antithrombotic therapy increased by 425% in the entire background population.

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What were the main limitations of this study?

The main limitation of this study is its design. Retrospective case-control studies cannot demonstrate causality. In this study, antithrombotic drugs are associated with serious upper GI bleeds, but this does not mean that they are definitely the cause of those bleeds. The misallocation of subjects when investigators are considering which cases to include is a potential source of bias.

Another major limitation of the study is that there were only a small number of people in many of the sub-groups. For many of the antithrombotic therapies, alone or in combination, the CIs are wide and the estimate of the risk of a serious upper GI bleed is therefore imprecise. The study was also underpowered to identify sub-groups of patients with a particularly high or low risk of a bleed.

The authors acknowledge that data were not available for all potential confounders (e.g. smoking, high alcohol intake, use of over-the-counter NSAIDs). Selection bias may also have been possible as patients who were taking antithrombotic therapy may have been more likely to be admitted when they had symptoms of a GI bleed than those who were not.

It is unclear what doses and formulations of antithrombotic drugs were used in patients in the study. They may not have been the same as those used in UK practice and this could affect the risks of treatment.

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Where does this study fit with current practice?

There are few indications for the use of combination antithrombotic therapy. Clopidogrel is licensed for use with aspirin in non-ST-segment-elevation acute coronary syndrome (ACS) and ST-segment-elevation acute myocardial infarction (STEMI).

NICE has recommended that, in people with non-ST-segment-elevation ACS who have a moderate to high risk of myocardial infarction (MI) or death, low-dose aspirin plus clopidogrel should be continued for 12 months following the most recent attack, before reverting to low-dose aspirin alone.²

Studies examining the risks and benefits of combination treatment with aspirin and clopidogrel in patients with STEMI have been short and the optimal duration of treatment is unknown.⁴ Draft NICE guidance for the secondary prevention of MI advises that patients who have been treated with a combination of aspirin and clopidogrel in the first 24 hours after STEMI should continue to receive this combination for at least two weeks, and no longer than 12 months, before reverting to low-dose aspirin alone. If the patient has not been treated with aspirin plus clopidogrel during the acute phase, the combination should not be routinely initiated.⁴

This case-control study¹ adds to the evidence that any possible benefits of treatment with clopidogrel plus aspirin may be outweighed by an increased risk of bleeding, especially with prolonged use. The CHARISMA study found that, in a broad population of patients at high risk of cardiovascular (CV) events, clopidogrel plus aspirin was no more effective than aspirin alone in preventing major CV events, but it increased the risk of bleeding.^5,6 In the MATCH study, which included patients who had suffered a recent stroke or transient ischaemic attack (TIA), combination treatment with aspirin and clopidogrel had no significant benefit over clopidogrel alone for the prevention of vascular events, but again was associated with significantly more bleeding than clopidogrel alone.^7,8 More recently, the ACTIVE-W study was stopped early when it was found that clopidogrel plus aspirin was associated with a significantly greater risk of major CV events and bleeding compared with warfarin in patients with atrial fibrillation at moderate to high risk of stroke.^9,10

Modified-release (MR) dipyridamole is licensed for use in combination with aspirin for the secondary prevention of stroke and TIA. NICE advise that this combination treatment should continue for two years from the most recent event, provided it is tolerated, before reverting to low-dose aspirin alone.³ This case-control study¹ is reassuring as the odds of having a serious upper GI bleed whilst taking aspirin and dipyridamole together were only slightly higher than for either drug alone. This is consistent with other studies. In the ESPRIT and ESPS-2 studies, there were no significant differences between the combination of aspirin and dipyridamole and aspirin alone in the incidences of bleeding.^8,11-13

Aspirin plus warfarin can reduce the risk of serious CV events compared with aspirin alone in patients with coronary artery disease, but it increases the risk of major bleeding.¹⁴ The combination should only be used under specialist supervision. Provisional recommendations for the place of aspirin plus warfarin treatment in the secondary prevention of MI are outlined in the draft NICE guideline.⁴

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Should this study change practice?

This case-control study¹ suggests that combination antithrombotic regimens should only be used with caution for conditions where it has been established that the benefits outweigh the increased risk of bleeding, and then only for a limited time. It may be useful to include the length of combination treatment courses, and the date when treatment should cease, on prescriptions, discharge summaries and labels.

The combinations of aspirin plus warfarin and aspirin plus clopidogrel appear to be associated with significantly higher incidences of serious upper GI bleeds than the individual antithrombotic drugs. These combinations should be used with care, as the risk of major bleeding may outweigh any benefits (e.g. reductions in CV events).

The study is consistent with NICE guidance for the use of aspirin with clopidogrel, which states that this combination should be considered for 12 months in non-ST- segment-elevation ACS, before reverting to low-dose aspirin alone.² Final NICE guidance on the secondary prevention of MI is due to be published in March 2007, and is expected to lead to further indications for combination antithrombotic therapy.

NICE guidance for the use of dipyridamole-MR plus aspirin is also reinforced by this study, as the benefits for the secondary prevention of stroke or TIA are likely to outweigh the modest increased risk of upper GI bleeding. Treatment with dipyridamole-MR plus aspirin should continue for two years from the most recent event, before reverting to low-dose aspirin alone.³

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References

1. Hallas J, Dall M, Andries A, et al. Use of single and combined antithrombotic therapy and risk of serious upper gastrointestinal bleeding: population based case-control study. BMJ, doi:10.1136/bmj.38947.697558.AE (published 19th September 2006)
2. National Institute for Clinical Excellence. Clopidogrel in the treatment of non-ST-segment-elevation acute coronary syndrome. Technology appraisal guidance 80. July 2004. Accessed from www.nice.org.uk on 27/09/06
3. National Institute for Health and Clinical Excellence. Clopidogrel and modified-release dipyridamole in the prevention of occlusive vascular events. Technology appraisal guidance 90. May 2005. Accessed from www.nice.org.uk on 27/09/06
4. National Institute for Health and Clinical Excellence. Secondary prevention in primary and secondary care for patients following a myocardial infarction. NICE guideline: draft for consultation. August 2006. Accessed from www.nice.org.uk on 27/09/06
5. Bhatt DL, Fox KAA, Hacke W, et al. Clopidogrel and aspirin versus aspirin alone for the prevention of atherothrombotic events. New Engl J Med 2006;354:1706–17
6. National Prescribing Centre. Clopidogrel found lacking in CHARISMA. MeReC Extra 2006:22. Accessed from www.npc.co.uk/merec.htm on 4/10/2006
7. Diener HC, Bogousslavsky J, Brass LM, et al. Aspirin and clopidogrel compared with clopidogrel alone after recent ischaemic stroke or transient ischaemic attack in high-risk patients (MATCH): randomised, double-blind, placebo-controlled trial. Lancet 2004;364:331–7
8. National Prescribing Centre. Prescribing antiplatelet drugs in primary care. MeReC Bulletin 2005:15;21–4. Accessed from www.npc.co.uk/merec.htm on 4/10/2006
9. The ACTIVE writing group on behalf of the ACTIVE investigators. Clopidogrel plus aspirin versus oral anticoagulation for atrial fibrillation in the Atrial fibrillation Clopidogrel Trial with Irbesartan for prevention of Vascular Events (ACTIVE W): a randomised controlled trial. Lancet 2006;367:1903–12
10. National Prescribing Centre. Warfarin superior to clopidogrel plus aspirin in AF: ACTIVE W. MeReC Extra 2006:24. Accessed from www.npc.co.uk/merec.htm on 4/10/2006
11. The ESPRIT study group. Aspirin plus dipyridamole versus aspirin alone after cerebral ischaemia of arterial origin (ESPRIT): randomised controlled trial. Lancet 2006;367:1665–73
12. National Prescribing Centre. ESPRIT supports current NICE guidance. MeReC Rapid Review 2006:1. Accessed from www.npc.co.uk/merec.htm on 4/10/2006
13. Diener HC, Cunha L, Forbes C, et al. European Stroke Prevention Study 2. Dipyridamole and acetylsalicylic acid in the secondary prevention of stroke. J Neurol Sci 1996;143:1–13
14. Gami A. Secondary prevention of ischaemic cardiac events: oral anticoagulants in addition to antiplatelet treatments. Clinical Evidence. December 2005. Accessed from www.clinicalevidence.com on 27/09/06

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