Stroke in Ireland – Facts and Figures
Each year, approximately 10,000 people are admitted to hospitals in Ireland with acute stroke and around 2,000 die – more deaths than breast cancer, prostate cancer and bowel cancer combined. An estimated 30,000 people are living in the community with disabilities as a result of a stroke. This makes stroke the third biggest cause of death in Ireland and the biggest cause of acquired disability.
Atrial fibrillation (AF) is the most common sustained heart rhythm condition, affecting around 1% of the total population worldwide with one in four adults over 40 developing the condition in their lifetime. Its prevalence increases with advancing age, affecting up to 5% of the population over 65 years, rising to 10% of the population 80 years and older. There are up to 57,000 people living with AF in Ireland and it is believed that up to 50% of suffers are unaware they may have the condition.1
AF is one of the most common risk factors for stroke and is associated with approximately one in six strokes globally. These strokes tend to be especially devastating with half of the people suffering an AF-related stroke dying within one year and many survivors facing persistent severe disability. AF increases risk of stroke up to 5 times with those at highest risk suffering from a previous stroke or transient ischaemic attack. Many AF-related strokes can be prevented with appropriate antithrombotic therapy.
Warfarin
Warfarin, a vitamin K antagonist, has been the long-time standard of care for stroke prevention in AF for the past 50 years and has been shown to reduce the risk of stroke by approximately 64% compared to placebo in well-controlled patients.
However, due to the problems associated with warfarin, such as the need for regular monitoring and dose adjustments, bleeding complications, and various food-drug and drug-drug interactions, only half of eligible patients (51%) receive treatment and fewer than half of these patients (approximately 25% of all patients) are controlled within the required narrow therapeutic range, representing a significant unmet need in stroke prevention in AF. People outside this therapeutic range have an increased risk of stroke or bleeding. Intracranial bleeding is the most serious and lethal complication of oral anticoagulation and is a major clinical concern in the treatment of elderly patients.2,3
Novel Oral Anticoagulants
Anticoagulation therapy is recommended in all patients with AF regardless of the level of stroke risk, other than lone AF or contraindications. Over the last number of years, several novel oral anticoagulants (NOACs) have been licensed in Ireland for the prevention of stroke and systemic embolism in adult patients with non-valvular AF (NVAF) with one or more risk factors. Currently approved agents are dabigatran (Pradaxa), rivaroxaban (Xarelto), apixaban (Eliquis), and edoxaban (Lixiana). Dabigatran is a direct inhibitor of thrombin, while rivaroxaban, apixaban and edoxaban are direct inhibitors of factor Xa.
Significant advantages of NOACs include (a) more predictable pharmacokinetic/pharmacodynamic profile and reduced susceptibility to food and drug interactions facilitating consistent, predictable anticoagulation levels without the routine coagulation monitoring required with warfarin; and (b) relatively rapid onset and offset of action, which remove the need for bridging therapies such as heparin and can facilitate management of patients requiring surgery or interventions. NOAC efficacy and safety has been established in several large phase III clinical trials (see opposite page). Compared with warfarin therapy, NOAC efficacy is non-inferior or superior for stroke prevention in patients with NVAF, with similar or lower levels of major bleeding.4-8
Reversal of Anticoagulant Activity
The major side effect of anticoagulation is bleeding. Whereas warfarin anticoagulation can be reversed (using vitamin K therapy or through administration of fresh frozen plasma [FFP] or prothrombin complex concentrate [PCC]), there were no specific reversal agents available for any of the NOACs until recently. Although NOACs provide good clinical outcomes in stroke prevention, serious bleeding remains a major concern for patients and physicians.
Idarucizumab (Praxbind) is a humanised monoclonal antibody fragment that has been developed as a specific reversal agent for dabigatran, and is now available in Ireland. It binds dabigatran with an affinity that is 350 times higher than the affinity of dabigatran for thrombin. Consequently, idarucizumab binds free and thrombin-bound dabigatran and neutralises its activity. Several clinical studies have shown that administration with idarucizumab produced immediate and complete reversal of the anticoagulant effects of dabigatran in healthy volunteers and in patients who had serious bleeding or required an urgent procedure.
In the absence of a specific reversal agent for the other NOACs, PCCs should be considered as part of a multimodal approach to management of major bleeding episodes in NOAC-treated patients with life-threatening bleeding along with haemodynamic and haemostatic resuscitation. Their potential pro-thrombotic effects also need to be considered.5
Besides idarucizumab, other reversal agents are in clinical development to reverse both dabigatran and the other NOACs. These include andexanet alfa, a recombinant truncated form of enzymatically inactive factor Xa, which binds and reverses the anticoagulant action of the factor Xa inhibitors, and PER977 (ciraparantag), a synthetic small molecule that is reported to bind to all of the NOACs and has been shown to reduce the whole-blood clotting time to background levels in volunteers given edoxaban.
Although there is less serious bleeding with the NOACs than with vitamin K antagonists, the lack of specific reversal agents has raised concerns about the inability to promptly reverse their anticoagulant effect in patients with life-threatening bleeding and in those requiring emergency surgery. The availability of a specific reversal agent for dabigatran, and the impending availability of other specific reversal agents for the NOACs should allay these concerns and encourage an increase in appropriate stroke preventive therapy for patients with NVAF.4-8
References: 1. Irish Heart Foundation Cost of Stroke in Ireland, September 2010. 2. Lloyd-Jones DM et al. Circulation 2004;110:1042-6. 3. Fuster et al. Circulation 2006; 114:700-52.4. Hanley CM and Kowey PR. J Thorac Dis 2015;7(2):165-171. 5. Sarich et al. Am Heart J 2015;169:751-57. 6. Pollack et al. Thrombosis and Haemostasis 114.1/2015. 7. Eikelboom et al. Circulation. 2015;132:2412-2422. 8. Pollack et al. N Engl J Med 2015;373:511-20.
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