The European Society of Cardiology
Recent trials in atrial fibrillation: lessons learned beyond rate and rhythm
Department of Internal Medicine III (Cardiology), University of Freiburg, Hugstetter Str. 55, Freiburg, Germany
* Christoph Bode, Department of Internal Medicine III (Cardiology), University of Freiburg, Hugstetter Str. 55, 79106 Freiburg, Germany. Tel.: +49-761/270-3441; fax: +49-761/270-3200
bode{at}mm31.ukl.uni-freiburg.de
Abstract
Atrial fibrillation (AF) is a common disorder, responsible for the majority of hospitalizations due to arrhythmias. It is well established that AF predisposes patients to the development of thrombi and a markedly increased risk of ischaemic stroke. The prevalence of AF increases dramatically with age, and, as the overall population ages, AF will become an increasingly important cause of morbidity and mortality. Numerous prospective randomized studies have shown that oral anticoagulation is an effective means for primary stroke prevention (risk reduction [RR] 62%) as well as secondary RR. Aspirin is also effective but to a lesser degree than oral anticoagulation. In a meta-analysis of six clinical trials, aspirin reduced the risk of stroke by approximately 20%. The risk reduction with aspirin just achieved statistical significance and there was considerable variability in the effects of aspirin in the individual trials, with only one of the six trials demonstrating a statistically significant reduction in the risk of stroke with aspirin. The balance between efficacy for stroke prevention and safety with regards to bleeding complications is best achieved at a target international normalized ratio of 2.0–3.0. This has been confirmed by several prospective studies and retrospective analyses. Trials evaluating rate control versus rhythm control strategies in AF have reinforced the need for continued anticoagulation. The AFFIRM (Atrial Fibrillation Follow-up of Rhythm Control Management) and RACE (Rate Control Versus Electrical Cardioversion) trials have demonstrated a high rate of stroke even in ‘rhythm-controlled’ patients and have given the medical community reason to reconsider the cessation of anticoagulation in cardioverted patients. However, ultimately, the fear of bleeding complications, specifically intracranial haemorrhage, has resulted in the underuse of anticoagulation despite its proven efficacy. The recent American College of Cardiology/American Heart Association/European Society of Cardiology guidelines for the management of AF recommend an individualized approach based on the estimated risk for stroke and bleeding during anticoagulation. Newer agents with more predictable anticoagulation, and thus expected improvement of the risk/benefit ratio, may not only help clinicians meet the guideline recommendations but also expand the number of patients eligible for highly effective stroke-preventive treatment.
Key Words: Stroke prevention • Oral vitamin K antagonists • Non-valvular atrial fibrillation • Aspirin • Anticoagulation • Haemorrhagic stroke
Introduction
Atrial fibrillation (AF) is the most common form of arrhythmia, affecting more than 2 million people annually in the USA.1 The most serious consequence of AF is stroke, which arises as a result of embolization of thrombi within the fibrillating left atrial appendix (Fig. 1).
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The prevalence of AF increases dramatically with increasing age.2,3 The Framingham Heart Study found that the rate of AF increases from just 0.5% in patients aged less than 60 to 9% in patients aged over 80.3 AF is therefore likely to be a growing health problem as life expectancy continues to increase; in fact, it is estimated to increase 2.5-fold during the next 50 years.
Risk factors and risk prediction for stroke in AF
Increasing age is not only a risk factor for AF but also an independent risk factor for stroke in AF. This was highlighted by the Framingham Heart Study, which found that the risk of stroke increased significantly from 1.5% in patients aged less than 60 to 24% in patients aged 80 and over.3 Other risk factors for stroke in AF include hypertension, female gender, prior stroke or transient ischaemic attack, and diabetes.1,4
Recently, a new risk stratification scheme for patients with new-onset AF has been proposed to predict the risk of stroke or death.1 This scheme was developed from evaluating the community-based patient population followed in the Framingham Heart Study. An absolute estimate for stroke alone was determined based on the five risk factors cited earlier, with points being assigned to each risk factor (Fig. 2), and the total score was used to produce an estimate of 5-year risk in individual patients (Fig. 3). Using this scoring system, a 75-year-old woman with diabetes, but with no prior stroke and normal blood pressure, for example, will have 16 points, reflecting a 24% risk of experiencing a stroke in the next 5 years. Similarly, the risk score for stroke or death can be estimated using the point score system supplemented with additional risk factors such as smoking, prior myocardial infarction (MI) and left ventricular hypertrophy.1 The incremental influence of selected risk factors on the risk of stroke or death for 60- and 70-year-old patients with AF are shown in Fig. 3 and clearly demonstrate that patients with 1 or more risk factors are at high risk of stroke.
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Treatment strategies
The risk prediction scheme described above is important for the identification of AF patients at a low or high risk of stroke, which will aid clinical decisions regarding assignment to certain therapies. What are the treatment options available for high-risk patients? The antiplatelet agent aspirin has been evaluated in several placebo-controlled trials. A meta-analysis of these trials demonstrated that aspirin produces a relative risk reduction (RR) of 22% (95% CI=2–38%) in patients with AF, although there was considerable variability between trials and in only one individual trial was there a statistically significant reduction.5 Anticoagulation therapy with the oral vitamin K antagonist warfarin, however, is superior to aspirin for stroke prevention. A meta-analysis of warfarin trials showed that warfarin provided a 62% relative RR when compared with placebo,5 while a meta-analysis of comparative trials of warfarin versus aspirin demonstrated a 36% relative RR for stroke with warfarin, when compared with aspirin (Fig. 4). 5
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These trials suggest that oral anticoagulation is the preferred treatment for stroke prevention from the point of view of efficacy; however, the risk/benefit ratio must be taken into account because of the haemorrhagic complications associated with warfarin treatment. To minimize the risk of bleeding, particularly in elderly patients, the lowest possible effective dose must be supplied. Fig. 5 shows the adjusted odds ratios for intracranial bleeding6 and ischaemic stroke7 plotted in relation to the intensity of anticoagulation.8 It can be seen that if anticoagulation is low the risk for stroke is high. When anticoagulation reaches an international normalized ratio (INR) of 2.0, the risk for ischaemic stroke is reduced and remains low.7 At an INR greater than 3.0, however, the risk of intracranial bleeding increases significantly.6
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The American College of Cardiology (ACC)/American Heart Association (AHA)/European Society of Cardiology (ESC) guidelines for the management of patients with AF recommend that the maximum protection against ischaemic stroke, with a low risk of bleeding, is achieved with an INR of 2.0–3.0.8 This INR range is a relatively narrow therapeutic window, which requires close INR monitoring.
The target INR range of 2.0–3.0 for optimal efficacy for stroke prevention and safety with regard to bleeding complications has been confirmed in a number of controlled trials.9–13 Although the target INR was different in the individual trials, the majority of ischaemic strokes in these trials occurred in patients whose INR was lower than 2.0 (Fig. 6). Furthermore, in all the trials, the majority of haemorrhagic strokes occurred when patients were intensely treated with anticoagulation therapy (that is, beyond an INR of 3.0). The shaded area in Fig. 6 highlights that the optimum safety and efficacy is achieved within the recommended INR range of 2.0–3.0. However, these trials also demonstrated that this range is relatively difficult to achieve, with many patients receiving either inadequate anticoagulation or over-coagulation.9–13
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Continued anticoagulation during treatment of AF by rate control or rhythm control strategies
Several recent studies have addressed the question of which treatment strategy – rate control or rhythm control – is superior in the management of AF.14,15 One of the key findings to emerge from these studies was the need for continued anticoagulation in both treatment strategies. For example, in the RACE (Rate Control Versus Electrical Cardioversion) trial, the strategy of rate control was compared with rhythm control in patients with persistent AF after a previous electrical cardioversion.14 Overall, 6.7% of patients experienced stroke – 5.5% in the rate control arm and 7.9% in the rhythm control arm. This indicates that rhythm control therapy offers no advantage for stroke prevention. Also, almost a third of the patients in the rhythm control arm experienced these events after discontinuation of warfarin. Most of these patients were in sinus rhythm, which suggests that anticoagulation treatment should be continued in patients with AF, even if cardiac rhythm appears normal. Another important observation from this trial was that 4.4% of patients, out of the 6.7% who experienced stroke, had an INR which was sub-therapeutic (INR less than 2.0). Also, most bleeding events occurred because of over-anticoagulation in patients whose INR was more than 3.0.
Similarly, the AFFIRM (Atrial Fibrillation Follow-up of Rhythm Control Management) trial investigated the two treatment strategies in patients with AF who were aged at least 65 or who had other risk factors for stroke and death.15 Patients were randomized to either rhythm control or rate control therapy, with both groups receiving warfarin for anticoagulation. There was no difference in the composite end point of death, disabling stroke, anoxic encephalopathy, major bleeding or cardiac arrest between the two arms. Out of 73% of patients in this trial who experienced ischaemic stroke, 55% of events occurred after warfarin treatment was stopped,15 providing further evidence that it is not safe to discontinue warfarin in patients at a high risk of thromboembolic complications. In accordance with the results from RACE, patients who experienced stroke while on warfarin had an inadequate INR of less than 2, and 69% of strokes occurred during sinus rhythm, again suggesting that rhythm control does not protect against stroke. Overall, trials such as RACE and AFFIRM have given the medical community reason to reconsider the cessation of anticoagulation in cardioverted patients.
Use of anticoagulation treatment
Despite the considerable evidence from clinical studies of the benefits of oral anticoagulation, the fear of bleeding complications, specifically intracranial haemorrhage, has meant that anticoagulation is underused. The ATRIA (Anticoagulation and Risk Factors in Atrial Fibrillation) study assessed the rates of warfarin use for stroke prevention in over 11000 patients with AF,16 The study found that 55% of patients used warfarin in the 3 months before or after their index date. Furthermore, it was found that warfarin use varied with age. The lowest rates of 44% and 35% were seen in the youngest (under 55 years) and oldest (85 years and over) age groups, respectively, and the higher rates ranging from 57% to 61% were seen in patients aged 55–84. In a subgroup of 1710 patients, considered ‘ideal’ candidates for anticoagulation because they were aged 65–74, had the risk factors of a previous stroke or hypertension (or both) and had no contraindications to warfarin – only 62% were receiving warfarin. Considering that increasing age is a risk factor of stroke for people with AF, the age group of 85 years and over are the patients that would derive the most benefit from anticoagulation, but, as mentioned previously, this was the most under-treated age group at just 35%.16 The significant drop-off in use in the elderly population is most likely due to concerns over the increased risk of bleeding, but the risk of stroke in the elderly is also higher, so the net clinical benefit is thus in favour of anticoagulation. Encouraging data from two US national registries, however, indicate that the situation is slowly improving, with warfarin use increasing from just 15–20% in 1990 to 55–60% today.17 Despite this steady improvement, there is still a long way to go in achieving the substantial health benefits that would result from greater adoption of anticoagulation for stroke prevention in AF.
The combined recommendations of the ACC, AHA and the ESC suggest that aspirin treatment is adequate to prevent adverse events in patients aged under 60, or patients aged over 60 with no additional risk factors, no heart failure, left ventricle ejection fraction less than 25% and no history of hypertension.8 It is recommended that oral anticoagulation is administered in patients: aged over 60 with diabetes mellitus or coronary artery disease (INR 2.0–3.0); aged over 75, especially women (INR 2.0); or with additional risk factors for stroke such as hypertension (INR above 2.5) or prior thromboembolism (INR above 2.5).
Summary
The incidence of AF is high, especially in the elderly; and, as our overall population ages, stroke associated with AF will become an increasingly important clinical problem. Anticoagulation therapy is more efficient than aspirin for reducing the risk of stroke in patients with AF. Despite this, anticoagulation agents such as warfarin are underprescribed in eligible patients, mainly because of safety concerns about haemorrhagic complications. However, these types of complications typically only occur because of intensive treatment beyond an INR of 3, and guidelines recommend that if patients are maintained at an INR between 2 and 3 these agents are effective and safe. This still represents a major limitation, however, owing to the relatively narrow therapeutic window and the close anticoagulation monitoring required for this therapy.
Significant healthcare costs, morbidity and mortality may be preventable through complete application of the guidelines regarding anticoagulation therapy. However, the development of new, safer, more effective oral anticoagulants would reduce adverse events and widen the population of eligible patients, which would, in turn, improve compliance with guidelines by both patients and doctors.
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