In This Issue

• Introduction to a Global Research Initiative – Professor the Lord Kakkar
• Thromboembolic Risk in Chronic Atrial Fibrillation – Gregory YH Lip
• The Economic Burden of Atrial Fibrillation – Sylvia Haas, MD
• Emerging Advancements for Stroke Prevention in Atrial Fibrillation – Alexander GG Turpie

Introduction to a Global Research Initiative

The essence of the Garfield registry

Clinicians and researchers share the mission to ensure that scientific advances are incorporated as efficiently as possible into clinical treatment strategies in order that they can deliver real benefits to patients.

While numerous controlled clinical trials have demonstrated the effectiveness of oral anticoagulation treatment in atrial fibrillation (AF), there is still a reluctance among clinicians and patients to provide oral anticoagulation on a routine basis.¹ As a result, many patients in whom antithrombotic therapy may have the potential to prevent thromboembolic stroke are not given this treatment,² with potentially devastating consequences.

The ongoing Global Anticoagulant Registry in the Field (Garfield) is investigating real-life treatment patterns in newly diagnosed AF patients at risk for stroke. This registry is unique in that it will prospectively register newly diagnosed patients with non-valvular AF, irrespective of whether or not they receive treatment. AF patients who are at risk for cardioembolic stroke or systemic embolization and do not receive anticoagulant therapy because of contraindications, fear of bleeding, inability to comply with monitoring or dosing of oral anticoagulants will still be included. This is important since these patients, in whom oral anticoagulants cannot presently be prescribed, represent an early failure which may well be associated with a subsequent risk of stroke or systemic embolisation. All patients will be treated to usual local practice, without or with any anticoagulation and monitoring strategy being performed as to normal routine.

The Garfield registry design and scope

The Garfield registry is an academic research initiative, led by the Thrombosis Research Institute (London, UK) and a multi-disciplinary Steering Committee. It is being conducted in collaboration with a global investigator network and a distinguished group of AF experts as National Coordinators.

• Site enrolment in the first 19 countries began in December 2009
• Patients will be enrolled as 5 sequential independent cohorts of 10,000 patients and the follow-up period will be 2 years for each cohort
• An additional validation cohort of 5,000 patients will be recruited with the first cohort
• In order to ensure an appropriate representation of country specific AF care settings, the proportion of participating hospital sites, coagulation clinics, community and GP centres differs across countries
• Eligible patients are being enrolled on a consecutive basis

The results of this largest, global disease registry in 55,000 AF patients at risk for stroke will provide a real-world view of the clinical effectiveness and economic impact of current AF management, including anticoagulant treatment options. Garfield will allow us to identify persisting unmet needs and to quantify the real-life clinical and economic value of current and future treatment options in stroke prevention.

Professor the Lord Kakkar, MBBS (Hons), BSc, PhD, FRCS

References

1. Emmerich J, et al. European Heart Journal Supplements 2005;7(Supplement C):C28–C33.
2. Waldo AL, et al. J Am Coll Cardiol 2005;46:1729–36.

Thromboembolic Risk in Chronic Atrial Fibrillation

Gregory YH Lip, MD FRCP

It is clear that AF not only increases the risk of stroke and thromboembolism, but also that strokes occurring in AF patients are associated with substantially increased risk of mortality, disability and recurrence.¹ Irrespective of strategies for control of rate or rhythm, stroke prevention with appropriate thromboprophylaxis is central to the management of this common arrhythmia.

Improved mechanisms for risk stratification will be valuable

Since stroke risk is not homogeneous across all AF patients, risk stratification is of great importance to the effective implementation of prevention strategies. Unfortunately, many of the schemata for stroke risk assessment tend to classify a large proportion of subjects into the ‘moderate risk’ category where treatment guidelines recommend either warfarin or aspirin, and have only a modest predictive value for thromboembolism. Stroke risk stratification schemata that classify a large proportion of AF subjects as ‘moderate risk’ could potentially be of limited value, since current treatment guidelines recommend the use of either warfarin or aspirin in such patients, and this can sometimes cause confusion over which therapy should really be prescribed. Furthermore, classification as ‘moderate risk’ can sometimes be used as an excuse not to give anticoagulation, since the guidelines ‘allow’ aspirin. Given the availability of new oral anticoagulant drugs that overcome the shortcomings of warfarin, it may be necessary to develop new risk schemata which are better able to identify the ‘low risk’ category of patients where no antithrombotic therapy may be an option.

A new score to guide the need for anticoagulant therapy

High-risk patients who should have anticoagulation therapy are those with previous stroke or thromboembolism and those aged ≥75, as well as those with 2 or more of the following risk factors: diabetes, hypertension, age 65–74, heart failure (or moderate-severe left ventricular dysfunction) – and, probably, female gender and vascular disease. These risk factors can be expressed with an acronym, CHA₂D₂-VASc.² The high risk patients (CHA₂D₂-VASc score of ≥2) can be treated with oral anticoagulation. Those with one risk factor (CHA₂D₂-VASc score of 1) can be treated with oral anticoagulation or aspirin, although oral anticoagulation is suggested rather than aspirin. Low-risk patients (CHA₂D₂-VASc score=0) are those with no risk factors, and treatment with aspirin or no antithrombotic therapy is recommended. However, the data for aspirin in the latter category of patients is poor, with little demonstrable effect on reducing thromboembolism but increasing the risk for bleeding.

References

1. Stroke Risk in Atrial Fibrillation Working Group. Neurology 2007;69:546–54.
2. Lip GY, et al. Chest 2010;137(2):263–72.

The Economic Burden of Atrial Fibrillation

Sylvia Haas, MD

AF is the most common heart rhythm disturbance with an estimated lifetime risk of 1 in 4 for individuals aged 40 years and older.¹ The authors of the ATRIA study reviewed 17,974 diagnosed cases of AF in adults (45% aged 75 years or older) and estimated that the overall prevalence of AF in the United States was 0.95%. Prevalence ranged from 0.1% among adults younger than 55 years to 9.0% in those aged 80 years or older. The authors estimate that approximately 2.3 million US adults currently have AF and they project that this figure will increase to more than 5.6 million by the year 2050, with more than 50% of affected individuals aged 80 years or older. This would represent a 2.5-fold increase in cases of AF over the next 50 years, reflecting the growing proportion of elderly individuals.²

Improved management of AF would help to reduce the burden of stroke

Cardioembolic stroke is the most serious and debilitating complication of AF.³ AF patients have a 5-fold increased risk of stroke and account for 15–20% of all strokes. In the Framingham Study, the annual risk of stroke attributable to AF was 1.5% among patients aged 50–59 years and increased to 23.5% in those over 80 years. These figures clearly suggest that early diagnosis and effective management of AF would help to reduce the burden of stroke. Furthermore, the prevention of stroke with pharmacological or non-pharmacological therapies in high-risk patients has the potential to significantly reduce this huge economic burden. For example, in patients with AF, who are known to have a high risk of stroke, the cost of treating a stroke has been calculated to be almost four-fold greater than the estimated costs of prevention with anticoagulant therapy over a 10-year period.⁴

Clinical burden of cardioembolic stroke

A study of more than 500 patients in Germany showed that those who had suffered cardioembolic stroke had more severe clinical deficits on admission, worse recovery on discharge and increased length of hospital stay than those with non-cardioembolic stroke.⁵ Moreover, the mean costs of acute care were higher for cardioembolic stroke (€4890 per patient) than for non-cardioembolic stroke (€3550). In addition to being more severe, cardioembolic strokes are associated with a higher risk of recurrence than other types of stroke.⁶ AF is the cause of 50% of cardioembolic strokes. The increased severity of strokes in patients with AF compared with other strokes suggests that these patients will experience a greater impairment in quality of life than patients without AF. In the European Stroke Community Project, the presence of AF increased the risk of remaining disabled after a stroke by almost 50%.⁷ Data from the Copenhagen Stroke Study were used to investigate the impact of stroke on morbidity. Loss of ability to perform normal daily activities following stroke, and decline in neurological function were significantly greater in patients with AF compared with those without AF, both immediately after the stroke and after rehabilitation.⁸ In addition, AF was associated with a 20% increase in the length of hospital stay and a 40% decrease in the likelihood of discharge to home.

Quality-of-life impact of stroke in AF patients

The impact of a stroke on an individual can be expressed as a utility score in which health-related quality of life is scored on a scale of 0 to 10, where 10 represents perfect health and 0 represents death. Murphy et al. found that mild stroke yielded a higher utility score (9/10) than severe stroke (4/10).⁹ As AF-related strokes are more severe than strokes in patients without AF, this indicates that AF-related strokes result in lower utility scores (i.e. poorer health-related quality of life) than other types of stroke. In a study of the impact of stroke on quality of life in patients with AF, the average utility score was 9/10 for a mild stroke, 1/10 for a moderate stroke and 0/10 for a severe stroke; 83% of patients rated their quality of life after a severe stroke as equal to, or worse than, death.¹⁰ More than one-third of patients who experience a stroke will suffer from some level of permanent disability. Thus, stroke can have a devastating impact not only on the individual but also on carers and the families. Consequently, patients with AF are a key target population for reducing the overall burden of stroke on society. Coordinated efforts are needed to face the increasing challenge of optimal stroke prevention and rhythm management in patients with AF.

References

1. Lloyd-Jones DM, et al. Circulation 2004;110:1042-6.
2. Go AS, et al. JAMA 2001;285:2370–5.
3. Kannel WB, et al. Am J Cardiol 1998;82:2N–9N.
4. Lightowlers S, et al. Stroke 1998;29:1827–32.
5. Winter Y, et al. J Neurol 2009;256:954–63.
6. Ferro JM. Lancet Neurol 2003;2:177–88.
7. Lamassa M, et al. Stroke 2001;32:392–8.
8. Jorgensen HS, et al. Stroke 1996;27:1765–9.
9. Murphy R, et al. J Neurol Neurosurg Psychiatry 2001;70:679–81.
10. Gage BF, et al. Arch Intern Med 1996;156:1829–36.

Emerging Advancements for Stroke Prevention in Atrial Fibrillation

Alexander GG Turpie, MD

Alexander GG Turpie Professor of Medicine, McMaster University, Hamilton, ONT, Canada

Antithrombotic therapy, which can reduce the risk of cerebral embolism – and therefore the risk of stroke – is fundamental to the management of AF.

Vitamin K antagonists (VKAs) are recommended for patients with AF who are at moderate-to-high risk of stroke. The effectiveness of VKA therapy has been well-documented in numerous studies, which have demonstrated a relative risk of 64% compared with placebo and 37% compared with antiplatelet therapy. However, VKAs have a narrow therapeutic window, so that patients may have an increased risk of either AF-related stroke or bleeding if the target INR is not maintained. VKAs have a high degree of inter- and intra-patient variability due to the influence of genetic factors, drug-drug interactions, dietary intake of Vitamin K and underlying medical conditions. Thus, regular coagulation monitoring and dose adjustment, as well as lifestyle modifications, are necessary to ensure that the anticoagulant effect is maintained in the therapeutic range.

Limitations of vitamin K antagonists

Several studies have shown that, despite its established benefits, anticoagulant therapy is underutilized in patients with AF. This is likely to be due to the unpredictable nature of VKA therapy and the resulting concerns among patients and health professionals. As a result, there is a clear need for new oral agents that provide the benefits of VKA without its limitations. Ideally, these agents should bring a balance of safety and efficacy, confer a predictable anticoagulant effect without the need for coagulation monitoring and be free of significant food and drug interactions.

Targets for new anticoagulants

There are several points within the coagulation pathway that may serve as targets for novel anticoagulants. Thrombin (Factor IIa) plays a pivotal role in coagulation since it converts fibrinogen to fibrin and amplifies its own generation through feedback activation of Factors V, VIII, and XI. It is also a potent stimulus for platelet activation. Once bound to fibrin, thrombin promotes further coagulation and thrombus growth through continued local activation of clotting factors and platelets. Factor Xa is the key coagulation factor which amplifies the generation of thrombin several hundred fold. Factor Xa binds with activated Factor V to form the prothrombinase-complex and this, in turn, converts prothrombin to thrombin. Several novel oral anticoagulants targeting these mechanisms are currently in development (Table 1), the most advanced of which are the direct thrombin inhibitor, dabigatran and the Factor Xa inhibitors, rivaroxaban and apixaban.

Table 1

Direct thrombin inhibitors and Factor Xa inhibitors for AF

Medication	Action	Phase III Trial	Comparator	Design	n
Dabigatran	DTI	RE-LY	Warfarin	Non-inferiority	18,113
Apixaban	Anti Xa	AVERROES	Aspirin	Superiority	5600
		ARISTOTLE	Warfarin	Non-inferiority	15,000
Rivaroxaban	Anti Xa	ROCKET-AF	Warfarin	Non-inferiority	14,000
Edoxaban	Anti Xa	ENGAGE	Warfarin	Non-inferiority	16,500

Dabigatran has been evaluated in the RE-LY study of 18,113 patients with non-valvular AF and at least one additional risk factor for stroke who were randomized to one of two blinded twice-daily doses of dabigatran (110 and 150 mg) or open-label dose-adjusted warfarin (INR 2.0-3.0). Patients were followed for a minimum of 12 months (mean 2 years). RE-LY was a non-inferiority study, with superiority analyses on comparisons that demonstrated non-inferiority. The primary outcome was a composite of stroke, including haemorrhagic stroke, and systemic embolism. Major bleeding was the primary safety outcome. Both doses of dabigatran demonstrated significant benefits over warfarin. The 150 mg twice-daily dose was superior to warfarin with a similar safety profile. The 110 mg twice-daily dose was similar to warfarin in efficacy with a superior safety profile. Importantly, both doses of dabigatran reduced the risk of intracranial haemorrhage to approximately one third that of warfarin.

ROCKET-AF is a large Phase III study comparing a 20 mg once-daily dose of rivaroxaban with dose-adjusted warfarin (INR 2.0–3.0) in patients with non-valvular AF and a CHADS2 score of at least 2 – a patient population at greater risk of stroke than was studied in RELY. Patients with moderate renal impairment (calculated creatinine clearance 30—49 ml/min inclusive) randomized to rivaroxaban were given a reduced dose of 15 mg. ROCKET-AF has completed recruitment of over 14,000 patients and the results are anticipated by late 2010. Two Phase III studies with apixaban are ongoing. ARISTOTLE is a double-blind non-inferiority trial comparing 5 mg of apixaban administered twice daily with dose-adjusted warfarin (INR 2.0—3.0) in approximately 18,000 patients with non-valvular AF and at least one other risk factor for stroke. The results are expected in 2011. AVERROES is a double-blind superiority study comparing 5 mg of apixaban with ASA (81–324 mg) in approximately 5600 patients who are unsuitable for warfarin therapy. The results are expected in 2010. Studies with edoxaban, YM 150 and betrixaban are underway.

Potential of new anticoagulant agents in AF

The new anticoagulant drugs in development offer patients with AF a simple, convenient option that brings the potential for significant benefits over VKAs. Garfield, the registry of current management of AF worldwide, will define the population who will benefit from the new treatments and identify the reasons for current underutilization and sub-therapeutic anticoagulation. This information will result in improved management of AF reducing the burden on patients, their families, and healthcare systems. The availability of a safe, effective, and convenient anticoagulant therapy to replace VKAs will be a welcome advance of the treatment paradigm.

Forthcoming events