Stroke Prevention in Atrial Fibrillation

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The yearly incidence of stroke in patients with atrial fibrillation (AF) is approximately 5%, which is five times higher than in comparable populations in sinus rhythm (SR). The stroke risk largely depends on the underlying heart disease. In 'lone' AF (absence of heart disease) the stroke risk is only 0.5% per year, whereas in AF associated with rheumatic valvular heart disease (VHD), like mitral valve stenosis (MVS), it is very high. Oral anticoagulation (with warfarin, acenocoumarol and phenprocoumon) has shown to be effective in the prevention of thromboembolism in patients with valvular AF (VAF) and non-VAF (NVAF). Severe bleeding with warfarin is seen in one in 100 patients per year, which is double the risk of stroke in lone AF; therefore, anticoagulation is only indicated in AF patients with a stroke risk of 2% or more per year.

For several decades, oral anticoagulants have been used in the treatment and prevention of venous thrombosis. Oral anticoagulants block the vitamin K-dependent liver production of the plasma clotting factors II (prothrombin), VII, IX and X. They have a relatively narrow therapeutic window that requires close international normalised ratio (INR) monitoring - overdosing may result in life-threatening bleeding and underdosing inefficacy. Recently, some major improvements in the monitoring of oral anticoagulation have been made. The efficacy and safety of oral anticoagulation were found to be correlated with the reached INR values in trials in patients with AF, in those with artificial heart valves and in those after myocardial infarction (MI). Moreover, INR self-monitoring, which may even be more efficient than laboratory monitoring, has become a reality.

However, oral anticoagulation remains a laborious and poorly predictable therapy. Recently, oral direct thrombin inhibitors have been introduced. These agents lack the need for anticoagulant monitoring. In a large clinical trial on venous thromboprophylaxis, ximelagatran showed better efficacy than low molecular-weight heparin and in the large Efficacy and Safety of oral direct Thrombin inhibitor ximelagatran in patients with recent Myocardial damage (ESTEEM) study in coronary artery disease (CAD), ximelagatran plus aspirin showed superiority over aspirin alone. After a proper dose-finding study the drug was tested against warfarin in patients with AF in two large trials: Stroke Prevention using ORal Thrombin Inhibitor in atrial Fibrillation (SPORTIF)-III and SPORTIF-V.

In patients with NVAF, ximelagratran 36kg twice-daily in 3,407 patients in an open-label design and in 3,922 patients in a double blind set-up proved not inferior to warfarin (INR 2:3) in stroke prevention with similar major but less minor bleeding (see Table 1). Transient liver enzyme elevations were seen in up to 3% with 24mg, and 6% and 7% with 36mg twice-daily in the SPORTIF trials and ESTEEM, respectively, as was seen in previous trials. Recently, the new oral direct thrombin blocker dabigatran has been evaluated in a 12-week dose-finding warfarin-controlled study in 502 patients with AF. It shows an acceptable efficacy and safety profile, but liver enzyme elevation was only seen in less than 1% of patients being treated with dabigatran (see Table 2). These results are the basis for the very large phase-III trial of dabigatran versus warfarin (RELY).

Not only direct thrombin inhibitors have been tested for stroke prevention in AF. The novel once-weekly subcutaneous factor Xa-specific pentasaccharide idraparinux was compared with warfarin in the Prevention of Thromboembolic Events, Warfarin Versus Idraparinux (pentasaccharide) (AMADEUS) study of 5,700 patients. Unfortunately, this trial was prematurely terminated due to increased severe bleeding in idraparinux-treated patients. Possibly, the very-long-acting pentasaccharide cannot be adequately antagonised in case of bleeding. In the near future, oral factor-Xa inhibitors will become available and will surely be evaluated against warfarin in AF.

Besides novel anticoagulants, antiplatelet therapy has been evaluated in stroke prevention. Aspirin has also shown to be protective against stroke in AF with a relative risk (RR) reduction of 36% compared with placebo, much less than warfarin versus control (62% RR reduction). In direct comparison with warfarin, aspirin is less effective but can be used as an excellent alternative in patients not willing or capable of using the cumbersome oral anticoagulants. The platelet adenosine diphosphate (ADP)-receptor antagonist (RA) clopidogrel, which has a good track record in the invasive and non-invasive treatment of coronary artery disease (CAD), has been tested against warfarin in aspirin-treated patients with AF in the 6,500 patients Atrial fibrillation Clopidogrel Trial with Irbesartan for prevention of Vascular Events (ACTIVE)-W study. This trial has also been prematurely stopped due to lack of efficacy relative to warfarin. The other ACTIVE studies are continuing. ACTIVE-A is a randomised trial of aspirin plus clopidogrel versus aspirin alone in patients with AF not willing or capable to use oral anticoagulants. ACTIVE-I is a randomised trial of irbesartan versus placebo on top of other therapy in patients with AF participating in the other ACTIVE studies.

After new drugs may have been given registration for AF, it is very likely that warfarin will be replaced with these alternative, much easier to use drugs. Although the first results look promising, there are unexpected safety and efficacy problems - safety issues include bleeding and liver toxicity. Since warfarin use is associated with a yearly risk of at least 1% major bleeding, excess haemorrhagic complications of new drugs will not be easily found. Very long-acting drugs without proper antidotes, such as idroparinux, should be avoided. Liver enzyme elevations, although to a lesser extent, has been observed in early studies with statins, but this turned out to be a minor problem. Whether this will also be the case for newer drugs is unknown and should be further tested. If after treatment initiation frequent liver enzyme testing is necessary in the first six months, this will counterbalance the new drugs' potential advantages with regards to drug monitoring. Furthermore, only patients similar to those in the large trials will be eligible for the trade-in of warfarin, because safety data of the new drugs in other AF patients are lacking. If safety seems good in a broader patient population, the drugs may find their way for general use in AF. However, this process will take a while, and in the meantime aspirin-controlled studies (with agents such as clopidogrel, which has a more established safety profile than the new drugs) will be finished. Depending of the outcome, physicians willing to trade-in warfarin in their AF patients must decide which agent to choose.

Finally, non-pharmacological measures have been evaluated for stroke prevention in AF. For a long time routine electrocardioversion has been thought to be the cure for AF with subsequent discontinuation of antiarrhythmic drugs and oral anticoagulation. However, this strategy was not found to be superior to the combination of just rate control and proper oral anticoagulation. More sophisticated techniques include internal electro-ablation of the left atrium and occlusion of the left atrial appendage. The effect on stroke prevention of these interventions remains to be established.