Evaluation of Risk Factors for Stroke/Embolism and of Complications Due to Anticoagulant Therapy in Atrial Fibrillation
To the Editor:
In their article, Wehinger et al1 examined the relationship between risk factors and complications in patients with atrial fibrillation (AF) and receiving oral anticoagulation (OAC) therapy. They reported that the complication rate in AF patients on OAC is higher in patients >65 years of age, patients with diabetes, those taking >3 additional drugs per day, and those with hypertension.
Before 1990, antithrombotic therapy for prevention of ischemic stroke and systemic embolism in patients with AF was limited mainly to those with rheumatic heart disease and prosthetic heart valves.2 Anticoagulation was also accepted therapy for patients who had sustained ischemic stroke to prevent recurrence but was often delayed to avoid hemorrhagic transformation. Some advocated anticoagulation of patients with thyrotoxicosis or other conditions associated with cardiomyopathy and AF.3
OAC is effective in reducing stroke and embolism by 68% in patients with AF. OAC is particularly recommended if additional risk factors for stroke or embolism such as increased age, hypertension, diabetes, and previous stroke are present.4 However, other factors such as drug intake, drug interaction (especially nonsteroid anti-inflammatory drugs), or other problems influence this situation. In our clinical experiences, the hemorrhagic complication rate in AF patients on OAC associated with nonsteroid anti-inflammatory drugs was higher than in those with only OAC.
Nonrheumatic AF is the most common cause of embolism from the heart to the brain. However, AF may be responsible for a greater proportion of ischemic strokes in the very elderly.2 In the European Atrial Fibrillation Trial,3 anticoagulants reduced the risk of stroke by two thirds, from 12% to 4% per year, and of the primary outcome event by ≈50%, reducing the annual rate of events from 17% in control subjects to 8% in anticoagulant-allocated patients.5
AF not associated with valvular heart disease is common in elderly persons and is an important marker for stroke. There has been interest in chronic OAC therapy because cerebrovascular events in patients with nonvalvular heart disease are often of cardioembolic origin.6
OACs are indicated for primary and secondary prevention of recent transient ischemic attack or ischemic stroke in many patients with AF. The target intensity of OAC involves a balance between prevention of ischemic stroke and avoidance of hemorrhagic complications. Targeting the lowest adequate intensity of OAC to minimize the risk of bleeding is particularly important for elderly AF patients. Maximum protection against ischemic stroke in AF is probably achieved with an international normalized ratio (INR) range of 2.0 to 3.0, whereas an INR range of 1.6 to 2.5 appears to be associated with incomplete efficacy, estimated at ≈80% of that achieved with higher-intensity OAC.3,7,8⇓⇓ For patients with nonvalvular AF, an INR of 1.6 to 3.0 is efficacious and relatively safe. For primary prevention in most AF patients <75 years of age and for secondary prevention, an INR of 2.5 (target range, 2.0 to 3.0) seems reasonable. A target INR of 2.0 (target range, 1.6 to 2.5) is recommended for primary prevention in patients >75 years of age.3,9⇓ In our clinics, advancing age generally increases the risk of major hemorrhage in patients given OAC for stroke prevention. Therefore, those patients should be treated with dose-adjusted OAC (INR, 1.6 to 2.5).
In high-risk patients or when a series of procedures requires interruption of OAC therapy for a period >1 week, unfractionated or low-molecular-weight heparin may be administered intravenously or subcutaneously, respectively.3 Anticoagulants appeared to be more effective than aspirin.10 However, for low-risk individuals, aspirin is a reasonable alternative to anticoagulants.
In conclusion, OACs are indicated for patients with recent transient ischemic attack or ischemic stroke who are in AF. However, especially in use of OAC over much longer periods, one should be careful because of increased risk of the major hemorrhage in patients given OAC for stroke prevention. Also, in clinical practice, the need for antithrombotic therapy in patients with AF typically extends over much longer periods.
- ↵Wehinger C, Stöllberger C, Langer T, Schneider B, Finsterer J. Evaluation of risk factors for stroke/embolism and of complications due to anticoagulant therapy in atrial fibrillation. Stroke. 2001; 32: 2246–2252.
- ↵Wolf PA, Abbott RD, Kannel WB. Atrial fibrillation as an independent risk factor for stroke: the Framingham study. Stroke. 1991; 22: 983-988.
- ↵ACC/AHA/ESC guidelines for the management of patients with atrial fibrillation. Eur Heart J. 2001; 22: 1852–1923.
- ↵Warlow CP, Dennis MS, van Gijn J, Hankey GJ, Sandercock PAG, Bamford JM, Wardlaw J. Preventing recurrent stroke and other serious vascular events. Stroke: A Practical Guide to Management. London, UK: Blackwell Science Ltd; 1996: 567–573.
- ↵Biller J, Love BB. Ischemic cerebrovascular disease. In: Bradley WG, Daroff RB, Fenichel GM, Marsden CD, eds. Neurology in Clinical Practice. 3rd ed. Stoneham, Mass: Butterworth-Heinemann; 2000: 1157–1160.
- ↵Minematsu K, Yasaka M, Yamaguchi T. Optimal intensity of warfarin therapy for secondary prevention of stroke in patients with nonvalvular atrial fibrillation: a prospective, randomized, multicenter trial. Stroke. 1999; 30: 241.Abstract.
- ↵Koudstaal PJ. Secondary prevention following stroke or transient ischaemic attack in patients with nonrheumatic atrial fibrillation: anticoagulant versus antiplatelet therapy. In: Warlow C, van Gijn J, Sandercock P, eds. The Cochrane Database of Systematic Reviews. London, UK: British Medical Journal Publishing; 1995; issue 1.
In his contribution, Dr İyigün addresses important questions regarding oral anticoagulant (OAC) therapy: the role of nonsteroid anti-inflammatory drugs (NSADs); international normalized ratio (INR) target range; and the importance of number, kind, and degree of risk factors for stroke or embolism in patients with atrial fibrillation (AF).
In patients with chronic AF who are on OAC, sufficient and adequate pain control without the use of NSADs or pain killers, which interact with OAC, is an important prerequisite. If patients are not informed and educated and are poorly followed up, the intake of NSADs may result in mucosal damage with gastrointestinal bleeding. Additionally, drug interactions between NSADs and OAC therapy may lead to increased propensity of bleeding from gastrointestinal, vesical, and respiratory mucosa and the integumentum.1 Furthermore, not only NSADs but a variety of other drugs interact with OAC.2 Additionally, it is not only the type of medication but also the absolute number of substances a patient is taking that leads to increasing bleeding risk.3
Dr İyigün recommends a lower INR target range in older than for younger patients on the basis of the findings of Yasaka et al.4 In that study, however, only a small number of patients was investigated, the follow-up period was short, the distribution between sexes was uneven, and the prevalence of additional risk factors was not mentioned. Furthermore, Yasaka et al did not mention whether the prevalence of minor and major bleeding events differed between patients <75 and ≥75 years of age. On the contrary, a large case-control study showed that the risk of ischemic stroke in patients with OAC increases with decreasing INR values.1 In that study, >50% of the patients were >75 years of age. Furthermore, several studies that looked for the preventive effect of low-dose OAC had to be stopped prematurely because of an increased rate of stroke or embolism.5
It is well known that with an increasing number of risk factors, the number of thromboembolic and bleeding events increases, even if the INR target range is 2.0 to 3.0.1 Whether a higher INR target range reduces the risk of thromboembolism without leading to more bleeding complications is unknown. Because there are indications that at an INR value of >4.0 the bleeding rate increases significantly, the target range should not be elevated depending of the number of risk factors.1
The recommendation that OAC be given to patients with AF and transient ischemic attacks is not justified at the moment because there are no studies supporting this assumption. It is particularly difficult to investigate patients with transient ischemic attacks because of the heterogeneous causes and the episodic, short-lasting characteristics of these events.
Dr İyigün recommends heparin in high-risk patients or when procedures require interruption of OAC for >1 week. To the best of our knowledge, this recommendation is not based on data from the literature. In our institution, we follow the recommendation to give heparin before or after surgery only to AF patients with recent (<3 months) stroke or embolism.6
In conclusion, we propose that OAC be administered to patients in whom AF is accompanied by at least 1 risk factor for thromboembolism (arterial hypertension, diabetes, previous stroke, age >75 years). The INR target range should be 2.0 to 3.0, regardless of the patient’s age. The presence of multiple additional risk factors does not necessitate an increase in OAC dosage in patients >75 years of age. Patients >75 years of age do not require lower INR values than patients <75 years of age. Care should be taken that medication interacting with OAC be avoided.