NPC Archive Item: Is clopidogrel ACTIVE for atrial fibrillation?

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17th April 2009

Clopidogrel plus aspirin reduced the risk of a vascular composite end point compared with aspirin alone in people with AF who were at increased risk of stroke and for whom warfarin-like drugs were unsuitable. However, this benefit has to be balanced against a significant increase in the risk of major bleeding where the NNT to cause a major bleed was similar to that to prevent a major vascular event – around 42 over 3.6 years.

Clopidogrel is not licensed for use in patients with AF who are at a high risk of vascular events and who are unable for various reasons to take warfarin. Should it receive such a licence in the future, then the potential benefit would need to be weighed against the risk of major bleeding and take into account the patient’s baseline risk of a vascular event.

What is the background to this?
Atrial Fibrillation (AF) increases the risk of stroke. AF patients known to be at high risk of stroke are recommended to take a vitamin K antagonist, such as warfarin. But warfarin increases the risk of bleeding, needs regular monitoring and interacts with many drugs. Patients not suitable for, or unwilling to take, warfarin or AF patients at lower risk of stroke, are treated with aspirin. The magnitude of benefit conferred with warfarin varies with the inherent risk for stroke. Patients with AF who are at high risk, particularly those with previous stroke or TIA, are likely to gain most from treatment with warfarin as compared to aspirin. Anticoagulation instead of aspirin for 1000 patients with atrial fibrillation, who had a previous stroke or TIA, is estimated to prevent 48 strokes per year with an excess of 2 major extracranial haemorrhages. In contrast for low-risk patients with atrial fibrillation only 4 strokes would be avoided annually per 1000 patients who received warfarin.

Further information about AF is available from the cardiovascular floors of NPC.

What does this study claim?
In this ACTIVE A trial, the primary outcome of any major vascular event was reduced in the clopidogrel plus aspirin group. There were 832 events in the combined group (n=3772) compared to 924 in the aspirin only group (n=3782), relative risk (RR) 0.89 (95% confidence interval [CI] 0.81 to 0.98), P=0.01. The absolute risk reduction (ARR) is calculated as 2.38% giving the number needed to treat (NNT) as 42 over 3.6 years. The difference in the primary outcome was mainly due to a reduction in the risk of stroke.

There were 251 major bleeding events in the clopidogrel/aspirin group and 162 in the aspirin only group. This gives an ARR of 2.37% and a number needed to harm (NNH) of 42 over 3.6 years.

How does this relate to other studies?
There are two related studies: ACTIVE W and ACTIVE I. In ACTIVE W (n=6,706) clopidogrel plus aspirin was compared to oral anticoagulation therapy in patients with AF associated with at least one major cardiovascular risk factor.  The incidence of the primary outcome (stroke, non-central nervous system [CNS] systemic embolus, myocardial infarction [MI], or vascular death) in patients on oral anticoagulation (OAC) therapy was 4.9% vs. 7.0% in the clopidogrel/aspirin group giving an NNH of 47; RR 1·44, 95% CI 1·18 to 1·76, P=0·0003.The trial was stopped early after a median follow-up of 15 months due to a significantly greater risk of major cardiovascular events and bleeding in the clopidogrel group, as compared to the warfarin group.  The incidence of bleeding was significantly greater with clopidogrel plus aspirin compared with warfarin (19.3% vs. 16.5%; NNH=35; RR=1.21, 95% CI 1.08–1.35, P=0.001).   ACTIVE I includes patients enrolled into ACTIVE A or ACTIVE W. In this on-going study, the effect of irbesartan on the risk of vascular events is being compared to placebo in patients with AF.

A NICE clinical guideline on the management of AF is available and discusses the use of anticoagulation and warfarin where appropriate. Its Quick Reference Guide contains some useful algorithms.

So what?
Although warfarin therapy is not ideal, its potential benefits and risks in AF are well known. The ACTIVE A study has shown that if you treat 100 people like those in the trial with clopidogrel plus aspirin rather than aspirin alone, two will be prevented from having a major vascular event but two will have a major bleed.  Currently clopidogrel is not licensed for use in patients with AF who at a high risk of vascular events and who are unable for various reasons to take warfarin. Should such a licence be granted in the future, then the patient’s degree of clinical risk and the risk-benefit ratio of the clopidogrel/aspirin combination would have to be assessed carefully and explained to the patient.

Study details
The ACTIVE Investigators. Effect of Clopidogrel Added to Aspirin in Patients with Atrial Fibrillation. N Engl J Med. Published early online on 31 March 2009 (10.1056/NEJMoa0901301)

Design: Randomised, double-blind, multi-centre, phase III trial.

Patients: 7,554 patients with AF at enrolment or who had had at least two episodes of intermittent AF in the previous six months were randomised. Patients were also required to have at least one risk factor for stroke, such as aged 75 years or more, previous stroke or aged 55 to 74 years with diabetes mellitus or coronary artery disease. Patients were excluded if they needed a vitamin K antagonist or had a risk factor for bleeding.  Reasons for enrolment in the study included a specific risk of bleeding (22.9%), the physician’s judgement that an OAC was inappropriate (49.7%) and patient preference (26.0%).

Intervention: Clopidogrel 75mg daily (n=3,772).

Comparison: Matching placebo (n=3,782).

All patients received aspirin 75-100mg daily, although by 4 years only 81.1% of patients were taking it.

Outcomes: The primary outcome was any major vascular event (stroke, non-CNS embolism, MI, or death from vascular causes). Secondary outcomes were the individual components of the primary end point and a composite of the primary outcome and major bleeding.

Results: 43 patients (0.6%) were lost to follow-up. 16.3% of the clopidogrel plus aspirin group and 15.2% of the aspirin group stopped study medication prematurely at one year, rising to 39.4% and 37.1% at four years. Analysis of results was on an intention-to-treat basis. After a median follow-up of 3.6 years, there were 832 primary outcome events in the clopidogrel plus aspirin group versus 924 in the aspirin only group, RR 0.89 (95% CI 0.81 to 0.98), P=0.01. This was driven mainly by a reduction in the risk of stroke, RR 0.72, 95% CI 0.62 to 0.83, P<0.001. There was no difference in the risk of either death from vascular causes or death from any cause in the two groups (secondary outcomes).

Safety: There were 251 major bleeding events in the clopidogrel/aspirin group and 162 in the aspirin only group, RR 1.57 (95% CI 1.29 to 1.92), P<0.001. 42 patients in the combined group died from major bleeding compared to 27 in the aspirin group (P=0.07). The most common site for bleeding was the gastro-intestinal tract.

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