NPC Archive Item: Use of triple antithrombotic therapy increases the risk of bleeding four times post MI

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25 January 2010

An observational study found that, in patients with first-time MI, the risk of hospital admission for bleeding was four times higher in those taking triple antithrombotic therapy (aspirin, clopidogrel and warfarin) compared with those taking aspirin alone, with no benefit in all cause mortality. The risk associated with dual therapy with clopidogrel plus warfarin was similar to that that seen with triple therapy.

Level of evidence:
Level 2 (limited quality patient-oriented evidence) according to the SORT criteria.

Healthcare professionals should continue to follow NICE guidance. A combination of low-dose aspirin and clopidogrel 75 mg daily is recommended for acute coronary syndrome (ACS) and myocardial infarction (MI). Combination treatment should be continued for 12 months after the most recent acute episode of non-ST-segment-elevation ACS/MI and, if the combination is used in the first 24 hours, at least 1 month after the most recent acute episode of ST-segment-elevation ACS/MI. Patients undergoing percutaneous coronary interventions, such as stenting should usually receive low-dose aspirin with clopidogrel (or prasugrel▼) for up to 12 months after the procedure. It is unclear how patients with MI who also have an indication for warfarin should be managed.

Treatment with triple therapy (aspirin, clopidogrel and warfarin) or dual therapy with clopidogrel and warfarin should be prescribed on an individual basis only after thorough risk assessment and a discussion about the possible benefits and harms.

What is the background to this?
Antithrombotic drugs have been shown to reduce the risk of death and serious vascular events in patients with acute MI. However, use of combination antithrombotic therapy increases the risk of bleeding, which in turn is associated with increased morbidity and mortality. Research has generally focussed on the efficacy of antithrombotic drugs, rather than safety, and some combinations have not been studied therefore, the balance of risks and benefits is unclear.  This study examined the risk of admission to hospital for fatal or non-fatal bleeding in over 40,000 Danish patients previously admitted with first-time MI and treated with different combinations of aspirin, clopidogrel and warfarin.

What does this study claim?
During a mean follow-up of 476.5 days, 4.5% of patients were admitted to hospital with non-fatal bleeding, and 0.3% with fatal bleeding. The unadjusted incidence of bleeding was lowest in the aspirin alone group (2.6% per year) and highest in the clopidogrel plus warfarin (12.3% per year) and triple therapy (12.0% per year) groups.

Apart from warfarin monotherapy, all drug combinations were associated with an increased risk of admission for non-fatal or fatal bleeding, compared with aspirin alone, and the increased risk of bleeding was proportional to the number of drugs used. After adjusting for confounders, the numbers needed to harm (NNHs) were: 166 with warfarin alone, 116 with clopidogrel alone, 81 with aspirin plus clopidogrel, 45 with aspirin plus warfarin, 15 with clopidogrel plus warfarin and 13 with triple therapy. This means that for every 13 people treated with triple therapy, rather than aspirin alone, one additional person suffered a fatal or non-fatal bleed over 15 to 16 months.

The risk of death or recurrent MI was three times higher in patients admitted for non-fatal bleeding than in patients without non-fatal bleeding, supporting an association between bleeding and increased morbidity and mortality.

So what?
Observational studies are subject to bias and can only show association, not prove causality. However, this study included almost 41,000 patients and made adjustments for possible confounders (e.g. year of admission, age, sex, co-morbidity, concomitant medical treatment, percutaneous coronary intervention). In addition, it is probable that the prescribers weighed up the risks and benefits of combination antithrombotic therapy and only suggested such treatment for those not deemed to be at high-risk of bleeding, so the results may be conservative. Despite its limitations, in the absence of any higher quality evidence, the study provides important information regarding the risks of bleeding with antithrombotic therapy in patients with MI.

In patients with a first-time MI, dual therapy with clopidogrel plus warfarin and triple therapy were associated with three to four times the risk of hospital admission for bleeding compared with aspirin alone. In addition, the risk of recurrent MI or death was higher in patients with a non-fatal bleed. These combinations of antithrombotic should only be prescribed after balancing any possible benefit from reducing the risk of vascular events against the risk of increasing bleeding on an individual basis.

Dual therapy with aspirin plus clopidogrel increased the risk of bleeding by half, and aspirin plus warfarin almost doubled the risk, compared with aspirin alone. These combinations should only be used in situations where the benefits are considered to outweigh the risks, in accordance with NICE guidance (e.g. ACS, MI, stenting and atrial fibrillation) and following individual risk assessment. A combination of low-dose aspirin and clopidogrel 75 mg daily is recommended for both non-ST-segment-elevation ACS/MI (12 months) and ST-segment-elevation ACS/MI (at least 1 month after the most recent acute episode). In addition, patients undergoing coronary or carotid interventions e.g. stenting, should generally receive, low-dose aspirin plus clopidogrel for up to 12 months after the procedure. NICE guidance on AF advises against adding aspirin to warfarin because it provides no additional benefit.

As we discussed in a MeReC Bulletin, it is worth noting that there is no robust evidence to support the view that clopidogrel is a safer alternative to low-dose aspirin or that its use is associated with a lower risk of bleeding. This study found that the risk of bleeding was a third higher in patients taking clopidogrel alone than it was in patients taking aspirin alone. In the CAPRIE study bleeding was similar in the aspirin and clopidogrel groups. However, a ‘high‘ 325mg dose of aspirin was used. This dose is known to have a significantly higher risk of bleeding than aspirin 75mg, which is the dose generally used in Denmark, where this study was performed, and in the UK.

Further information is available on the cardiovascular section of NPC. A new floor on antiplatelet drugs is due to be launched later this year.

Study details:

Sorensen R, Hansen ML, Abildstrom SZ, et al. Risk of bleeding in patients with acute myocardial infarction treated with different combinations of aspirin, clopidogrel, and vitamin K antagonists in Denmark: a retrospective analysis of nationwide registry data. Lancet 2009;374:1967–74

Design: An observational study examining the risk of hospital admission for bleeding associated with different antithrombotic regimens using four national registers in Denmark.

Patients: 40,812 patients aged 30 years or older who had been admitted to hospital with first-time myocardial infarction between 2000 and 2005. Patients were eligible for inclusion if they had claimed a prescription of aspirin, clopidogrel, or warfarin within 90 days of discharge from hospital.

Intervention and comparison: Patients were allocated one or more of the following drug regimen groups: monotherapy with aspirin, clopidogrel, or warfarin; dual therapy with aspirin plus clopidogrel, aspirin plus warfarin, or clopidogrel plus warfarin; or triple therapy including all three drugs. For most patients, treatment regimens changed during the study period. Therefore, drug exposure groups were created as time-varying covariates. Patients were allowed in only one drug exposure group at a time, but could change groups during the study period according to claimed prescriptions. The risk of hospital admission for bleeding was assessed for each antithrombotic regimen. A bleeding endpoint was defined as an admission to a Danish hospital with a diagnosis of non-fatal bleeding (primary or secondary) or a diagnosis of bleeding as the cause of death (fatal bleeding).

Outcomes and results:
During a mean follow-up of 476.5 days, 4.5% of patients were admitted to hospital with non-fatal bleeding, and 0.3% with fatal bleeding.

Table: Risk of hospital admission for fatal or non-fatal bleeding in patients treated with antithrombotics after first-time MI

Unadjusted incidence (% per person-year) Adjusted NNH Hazard ratio (HR) 95% confidence interval (95%CI)
Aspirin 2.6% Reference 1.00 Reference
Clopidogrel 4.6% 115.7 1.33 1.11 to 1.59
Warfarin 4.3% 165.9 1.23 0.94 to 1.61Not significant
Aspirin plus clopidogrel 3.7% 81.2 1.47 1.28 to 1.69
Aspirin plus warfarin 5.1% 45.4 1.84 1.51 to 2.23
Clopidogrel plus warfarin 12.3% 15.2 3.52 2.42 to 5.11
Aspirin, clopidogrel and warfarin 12.0% 12.5 4.05 3.08 to 5.33

37.9% of patients with non-fatal bleeding had recurrent MI or died during the study period compared with 18.4% patients without non-fatal bleeding (HR 3.00, 95%CI 2.75 to 3.27).

Sponsorship: The Danish Heart Foundation and the Danish Medical Research Council.

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