Chapter 6 - Treating AF and preventing stroke

Key points

  • Direct treatment of AF is frequently necessary to control distressing and intrusive symptoms; some heart rhythm treatments also reduce the risk of stroke
  • It is recommended that patients receiving antiarrhythmic treatment for AF also receive therapy to reduce the risk of blood clots
  • Warfarin is safe, effective and cost effective for the prevention of stroke in the majority of AF patients
  • Warfarin is used less in the UK than recommended in authoritative guidelines; this under use results from practical obstacles and, frequently unfounded, safety concerns
  • High blood pressure and diabetes, which commonly affect patients with AF, also require management to reduce the risk of stroke

Aims of AF management

The immediate aim of AF clinical management concentrates on the relief of symptoms and the assessment of AF-associated long term risk. 116 The greater proportion of this document is focused on the serious complications of AF, specifically stroke. For many patients, however, addressing the symptoms of AF represents a much greater concern than preventing long-term complications. The symptoms of AF can be debilitating and unpredictable. Many AF patients report a dramatic fall in quality of life. As we have learned in previous chapters, many also suffer from a pronounced decline in mental health. At diagnosis, it is common for a patient to have endured a considerable period of time living in fear of symptoms over which they had no control and of which they had no understanding. Treatments such as ablation that achieve the desired symptomatic control by returning the heart to a normal rhythm also offer the potential benefit of eliminating the threat of long-term complications such as heart failure and stroke.

For these reasons, it is vital that the drugs and procedures that treat the underlying AF are used in appropriate patients whenever possible.

In a considerable proportion of patients, control of the AF itself proves unsuccessful and treatment becomes entirely targeted at assessing and reducing the risk that a patient will suffer serious long-term consequences of AF, particularly stroke and heart failure.

This chapter reviews current treatments both for AF directly and for managing the risk of long term complications independently of the underlying AF.

Rhythm and clotting

Two treatment approaches underpin the management of AF. One is to correct the faulty heartbeat, 178 and the other is to manage the risk of stroke by preventing the formation of clots in the fibrillating heart.

Rate control, rhythm control and cardioversion

Several strategies are commonly used to treat the heartbeat:

Strategies for treating a faulty heart rhythm

Rate control

Slowing an excessively fast pulse with sustained drug treatment

Rate control is used to treat symptoms and to relieve stress to the cardiovascular system

Rhythm   control

Returning the heart to a normal rhythm with sustained drug treatment

Rhythm control is achieved with antiarrhythmic drugs that reduce the fibrillation to control symptoms

Cardioversion

Resetting the heart rhythm suddenly, usually with an electric current

Ablation

Returning the heart to a normal rhythm permanently by surgically blocking chaotic electrical activity in the atria

Reducing the risk of stroke

Regardless of the course chosen to address the underlying heart rhythm problem, AF patients almost always need additional management of stroke risk by preventing clots from forming and blocking blood vessels in the brain.

AF disrupts the blood flow through the heart allowing the formation of a blood clot, or thrombus. Most strokes are the result of a thromboembolism which is a clot that travelled to the brain in the bloodstream. Strategies for the prevention of stroke in patients with AF primarily involve the use of anticlotting drug therapy. It is recommended that AF patients receiving treatment to correct their for heart rhythm also receive some form of anticlotting therapy 82

There are three main classes of ‘blood-thinning’ drugs currently used in the prevention of stroke in patients with AF

The main types of antithrombotic ('blood thinning') drugs

Anticoagulants

which interrupt the pathway of chemical reactions that result in the formation of a blood clot.

Warfarin is the recommended oral anticoagulant (OAC) for stroke prevention in AF patients

Antiplatelet drugs

which limit the aggregation of platelets; components of the blood that form a significant part of the blood clot.

Aspirin is the most widely used antiplatelet agent for the reduction of stroke risk in AF patients

Thrombolytics which break up blood clots once they are formed. Thrombolytics are generally reserved for use in the acute setting and do not play a role in long-term stroke prevention

 

Warfarin

Warfarin belongs to a class of drugs called vitamin K antagonists, (VKAs) meaning that they interfere with the normal action of vitamin K which is involved in the blood clotting process. Specifically, four proteins that play key roles in the blood coagulation pathway require vitamin K for their production. Warfarin inhibits the action of vitamin K, limiting the production of these four anticoagulation proteins. 4 17 The anticoagulation pathway is a series of enzyme-controlled chemical reactions that ultimately produces fibrin, an insoluble protein that combines with platelets to form blood clots.

A narrow effective range and a need for monitoring

Despite this useful anticoagulant activity, warfarin has only a narrow range of concentration in the blood in which it is both safe and effective. Maintaining warfarin within this range is also complicated by interactions with food and other drugs 18 that can significantly alter blood levels of warfarin regardless of the dose taken.

If the level of warfarin is too low then the patient is not benefiting from a reduced risk of stroke. If the level is too high, the anticoagulation properties put the patient as an increased risk of bleeding.

Thus, the management of patients on warfarin can be challenging, and frequent monitoring is required so that the dose can be adjusted to maintain effective and safe therapy. For monitoring, a measure of clotting time is taken (called the pro- thrombin time). If clotting takes too long then the dose needs to be reduced. If clotting happens too quickly, the dose of warfarin needs to be increased.

Understanding clotting time and INR

So that all pro-thrombin tests can be compared accurately with one another, the result of the test is converted to a ratio between the test result and a standard pro-thrombin time. This ratio is called the international normalised ratio (INR). Consequently, it is the INR that a physician and patient will try to keep within a target range to ensure warfarin remains at ideal levels in the blood. A target INR of 2.0 - 3.0 is typically recommended for patients receiving warfarin. 8 83 If the INR is too high, a patient is at increased risk of bleeding; too low, and the risk of a blood clot becomes high.

Drawbacks of warfarin are not insignificant and include unpredictable interactions with food which often necessitate significant lifestyle changes. One of the many drugs with which warfarin interacts is amiodarone, an anti-arrhythmic drug used in the treatment of AF. 84. The inconvenience of INR monitoring and frequent dose adjustment also represents a burden for many patients.

Efficacy of warfarin in clinical trials

Warfarin has been shown to be very effective at reducing stroke in AF patients. Systematic reviews of clinical trials in patients with AF have shown, compared with no therapy, that warfarin can provide a 62-68% reduction in stroke (Figure 9) and a 26-33% reduction in the death rate 85 87 88 without significantly increasing the risk of major bleeding. This means that for every 1,000 patients treated with warfarin, 31 strokes will be prevented each year. 85 Given the cost and harrowing consequences of stroke, this is an equations that strongly favours the use of warfarin.

Importantly for patients with AF, it has been shown that, when the dose is monitored and adjusted, warfarin is effective in preventing both mild and severe strokes. 89 90

Warfarin in clinical practice

The practical difficulties in maintaining the target INR, understandably raise concerns that the efficacy and safety observed with warfarin in clinical trials might not reflect what can be achieved in routine clinical practice. 91 Clinical trials monitor patients very closely, more than might be practical or possible in routine clinical practice. Also, to meet trial design and ethical requirements, clinical trials often exclude patients at high risk of bleeding while also recruiting relatively few elderly patients 85 91.

These concerns were largely refuted by observational studies that reviewed the history of large groups of patients cared for in routine clinical practice. In a large-scale study of more than 11,500 AF patients, warfarin provided a 39-60% reduction in the risk of thrombolembolic events (stroke and peripheral embolism) and a 31% reduction in the risk of death compared with either patients taking therapy or patients only taking aspirin. 92 The risk of an intracranial bleed was almost doubled with warfarin but still remained low; with no significant association between warfarin and non-intracranial bleeding. The authors concluded that the results of clinical trials of warfarin translate well into clinical care for patients with atrial fibrillation. 92

Further investigations in the clinical practice setting in Italy and the UK have demonstrated reductions in the risk of stroke of between 26-66% in patients with AF receiving warfarin compared with those not receiving warfarin. 93 95 Despite an increased risk of bleeding, the overall rates of ill health and death were significantly lower in the Italian patients receiving warfarin than in those not receiving warfarin. 94 95 However, the risk reduction observed in the UK study (26%) was substantially lower than in clinical trials. 94 Further analysis has highlighted management differences between anticoagulation clinic care and routine medical care, with patients in routine clinical care spending less time within the target INR range. 94 150 While the efficacy and safety profiles of warfarin do appear to be somewhat less favourable in routine medical practice than in clinical trials, the benefits outweigh the risks in the majority of patients.

Warfarin is currently recommended in UK and European guidelines as first-line therapy in patients with AF and a moderate or high risk of developing stroke. 8 83 Despite evidence that following the guidelines results in improved patient outcomes, 106 there is significant under-use of warfarin illustrating that the guidelines are not always followed. Thus, many patients with AF and a moderate-to- high risk of stroke do not receive anticoagulant therapy and therefore remain at high risk for stroke. 112 19

Improving warfarin use with GRASP-AF

As introduced in the previous chapter, GRASP-AF is a tool for GPs that automates the identification of patients for whom warfarin treatment should be started.  GRASP-AF data, collected from use in over 1,500 English GP practices, reinforces NICE data showing that only around half (55%) of those with AF at high risk of stroke are prescribed warfarin.

GRASP-AF is part of a broad NHS Improvement programme to raise awareness of AF and stroke risk, thereby reducing the number of AF-related strokes.  An important element of this work is improving the management of stroke risk in patients with AF by promoting appropriate risk assessment, and the prescribing of appropriate anticoagulation.  This is achieved through the use of the GRASP-AF tool that is free for GPs to download from the NHS Improvement web site. The GRASP-AF tool identifies patients with AF, calculates their stroke risk, and also details their current management. This information is simply summarised, allowing GPs easily to audit their current management of AF against best practice guidelines.

GRASP-AF also provides a facility to upload the data to CHART, a web-based comparative analysis tool available to all GPs. This provision enables anonymous comparison of data with other practices.  Local and regional analyses are also made possible by comparisons between Primary Care Trusts, Cardiac and Stroke Networks and Strategic Health Authorities. To date, 1,500 GP practices in England have run GRASP and uploaded their data to CHART. This growing database is probably the largest AF database in the world. Illustrating the potential that warfarin has to reduce stroke risk, GRASP-AF is already leading to improvements in anticoagulation and management of AF in general practice.

Cost of warfarin in stroke prevention in atrial fibrillation

In a UK study, the cost of preventing one AF-related stroke per year using warfarin was estimated to be £5,260. 96 This cost of prevention appears to be favourable when compared with a European average cost of €11,799 for treating a stroke. 62 In another study of patients with AF in the UK, the cost of treatment of a stroke over a 10-year period was estimated to be almost four times greater than the estimated 10-year direct costs of anticoagulation, 97 further indicating that prevention is a cost effective option, regardless of the costs associated with warfarin and its challenges. Numerous other studies have provided additional evidence that anticoagulation with warfarin is cost-effective in patients with AF at a moderate or high risk of stroke when compared with no therapy or aspirin. 105 99

As well as efficacy and safety, modern health providers also have to take into account the cost-effectiveness of a treatment. This can be challenging as it necessarily puts a price on human health and life. However, done carefully, cost-effectiveness comparisons allow many different treatments to be assessed on a level playing field. In the absence of unlimited funding, cost-effectiveness comparisons allow the NHS to make treatment decisions that will have the greatest benefit for the most people.

To make these comparisons, health economists use the QALY; a quality-adjusted life-year. To illustrate, a year in perfect health is equal to a QALY of 1. A year in less than perfect health would have a QALY less then 1. The worse the health, the closer the QALY becomes to zero.

Treatment of AF patients with warfarin has been found to be cost effective, i.e., associated with a low cost per QALY, particularly in patients considered to be at moderate-to-high risk of stroke. 99 In one study, the cost of warfarin for AF patients with one additional stroke risk factor was reported to be $8,000 per QALY saved 109  well below the threshold of acceptable cost effectiveness of £20,000 - 30,000 per QALY established by NICE in the UK. 100

It should be noted that the cost effectiveness of warfarin is dependent on achieving a significant reduction in the risk of stroke. Practical difficulties in maintaining target INR values may result in warfarin being less cost effective in clinical practice than in clinical trials. INR monitoring in clinical practice may also incur additional costs, to the patient, carer and society, not captured in the cost-effectiveness studies.

Thus, it is important that stroke prevention in clinical practice is improved so that it is as cost effective as in clinical trials. This might be achieved through new strategies that deliver optimal management with warfarin. It might also be achieved following technological advances, or new treatments that overcome the current challenges of warfarin.

Aspirin

One of many actions of aspirin is to reduce the activity of platelets during clotting. Limited platelet aggregation reduces the risk of a clot from forming which, in turn, helps to prevent a stroke. 101

In patients with AF, aspirin reduces the risk of all strokes by approximately 22% compared with placebo. For severe, disabling strokes, the reduction in risk with aspirin compared to placebo is smaller (13%). 86 Clinical trials directly comparing aspirin with warfarin in the prevention of stroke in AF have shown warfarin to be significantly superior, reducing the risk of a stroke by approximately half compared with aspirin. 107 129 Despite perceptions that it may be safer than warfarin, a major drawback of aspirin is that it increases the risk of bleeding, particularly in the gastrointestinal tract. 65 104

Aspirin is therefore recommended only in patients with a low risk of stroke and in those who cannot take warfarin. 8 83 It should be noted, however, that there is doubt as to the benefit of aspirin in patients at low risk of stroke. 108 98

Managing other conditions that increase stroke risk

AF commonly co-exists with other conditions, such as high blood pressure and diabetes, which themselves can contribute to the risk of blood clots and stroke. The risk in patients with several of these conditions is cumulative  that is, the more conditions that predispose to stroke, the greater the risk. Even in patients who are receiving antiarrhythmic and anticlotting therapy, effective management of these other conditions can further reduce the risk of stroke.

Blood pressure control is particularly important in the management of AF, as uncontrolled blood pressure increases the risk of stroke 3-fold. 68 110

AF in patients with diabetes is also associated with a very high risk of stroke. One study in patients with diabetes found that those who also had AF had a more than 60% greater risk of death from all causes than patients without AF; they also had an increased risk of death from stroke and heart failure. 111

It is therefore clear that conditions which increase the risk of stroke and that co-exist with AF must be carefully managed.

The outlook for stroke prevention in patients with atrial fibrillation

To summarise, patients with AF should be managed holistically and treated with drugs or other strategies that control the abnormal heart rhythm itself, as well as with anticlotting therapy to reduce the risk of blood clots and, hence, stroke. Warfarin has been shown to reduce the risk of stroke in patients with AF in both clinical trials and clinical practice. Importantly, warfarin has proven efficacy in reducing the risk of severe, fatal or disabling strokes. In addition, anticoagulation with warfarin has been demonstrated to be cost-effective in patients with AF and a moderate-to- high risk of stroke. Warfarin is, however, associated with major, well-recognised drawbacks. Nevertheless, it remains frontline therapy in this indication. Thus, in the immediate term, improved detection of asymptomatic AF and increased use and optimisation of warfarin therapy is important to reduce the incidence of severe strokes in patients with AF.

In the medium-to-long term, alternative therapies that combine convenience with a efficacy and safety could help to improve further the prevention of stroke in patients with AF. The development of such treatment promise considerable improvements in the management of patients with AF. Several clinical studies of potential new treatment are ongoing and early indications are positive. New and emerging treatments and recently-published clinical trial results are discussed in more detail in the chapter "New developments for stroke prevention in patients with atrial fibrillation".