Prevention of thromboembolism in patients with atrial fibrillation: the problem of oral anticoagulant choice

Atrial fibrillation (AF) is a leading cause of stroke in older adults. It affects 4.5 million people in the European Union and more than 3 million people in the United States, with the number of Americans with AF projected to increase to 7.5 million by 2050. The incidence of AF increases with age, so the problem of cardioembolic stroke is becoming increasingly common as the population ages.

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Stroke prevention in patients with non-valvular atrial fibrillation and chronic kidney disease

Chronic kidney disease (CKD) is common in patients with atrial fibrillation and may affect drug metabolism, bleeding, and stroke rates. Therefore, the choice of safe and effective therapy for atrial fibrillation requires an accurate assessment of renal function.

Results from randomized trials of stroke/systemic thromboembolism prevention support the use of oral anticoagulants in patients with a glomerular filtration rate of at least 30 mL/min/1.73 m2. Clinical trials of antiplatelet agents and oral anticoagulants in patients with atrial fibrillation have excluded patients with severe renal impairment (glomerular filtration rate <30 mL/min/1.73 m2), so treatment data for these patients are not available.

A retrospective analysis of 46 cohort studies (n = 41,425) in patients not necessarily with atrial fibrillation undergoing hemodialysis found an increase in mortality with warfarin (relative risk 1.27), clopidogrel (relative risk 1.24), and aspirin (relative risk 1.06).

In patients with atrial fibrillation receiving an oral anticoagulant, creatinine levels should be measured at least annually and glomerular filtration rate calculated. In chronic kidney disease and a glomerular filtration rate greater than 30 ml/min/1.73 m2, antithrombotic therapy is carried out in accordance with the CHADS2 stroke risk assessment according to the recommendations for patients with atrial fibrillation and normal renal function. With a glomerular filtration rate of 15-30 ml/min/1.73 m2 in the absence of dialysis, antithrombotic therapy is carried out according to the same principles, but warfarin is the preferred drug due to the lack of data on new anticoagulants in patients with chronic kidney disease. It is advisable to consider the possibility of reducing the dose of the selected drug. In patients with atrial fibrillation with a glomerular filtration rate of less than 15 ml/min/1.73 m2 and undergoing hemodialysis, oral anticoagulants and acetylsalicylic acid are not recommended for stroke prevention.

Predicting the risk of stroke

It is known that the risk of stroke and systemic thromboembolism in paroxysmal, persistent and permanent atrial fibrillation does not differ significantly, and is more influenced by other clinical factors. According to the CHADS2 stroke risk calculation system, patients with atrial fibrillation are assigned 1 point for chronic heart failure, arterial hypertension, age over 75 years and diabetes mellitus, and 2 points for a history of stroke or transient ischemic attack. Each additional point of the CHADS2 scale is accompanied by an annual increase in the stroke rate by approximately 2.0% (from 1.9% at 0 points to 18.2% at 6 points). Changes related to the detailing of risk assessment in patients with a low number of points were included in 2010 in the recommendations of the European Society of Cardiology on atrial fibrillation in the form of the CHA2DS2-Vasc system. Similar to CHADS2, the new system assigns 2 points to the age of a patient with atrial fibrillation over 75 years old and additionally gives 1 point for age 65-74 years, vascular diseases (previous myocardial infarction, atherosclerosis of peripheral arteries, large plaques in the aorta) and female gender. The recommendations of the European Society of Cardiology suggest using CHADS2 primarily, and CHA2DS2-Vasc - to clarify the probability of stroke at low risk (0-1 point according to CHADS2).

Risk of bleeding

The effectiveness of antithrombotic therapy for the prevention of ischemic stroke must be balanced against the risk of major bleeding, especially intracerebral bleeding, which can often be fatal. The risk of bleeding depends on the properties of specific antithrombotic drugs and various patient characteristics. Hemorrhagic risk will increase with increasing antithrombotic intensity of therapy, increasing sequentially from:

1. acetylsalicylic acid (75-325 mg/day) or clopidogrel (75 mg/day) in monotherapy, then
2. combinations of acetylsalicylic acid and clopidogrel, then
3. dabigatran 110 mg twice daily to
4. dabigatran 150 mg twice daily, rivaroxaban and vitamin K antagonists.

Apixaban therapy is associated with a lower risk of bleeding compared with vitamin K antagonists. For the latter, the risk of bleeding depends on the international normalized ratio (INR) during treatment, the quality of monitoring, the duration of treatment (high risk during the first few weeks), as well as the stability of dietary habits and the use of drugs that may alter the activity of therapy. The risk of bleeding is probably higher in general clinical practice than in strictly controlled clinical trials.

The 2010 European Society of Cardiology Atrial Fibrillation Guidelines include the HAS-BLED bleeding risk scoring system. Patients are assigned 1 point for hypertension, history of stroke or bleeding, labile INR, advanced age (over 65 years), liver or kidney dysfunction, use of drugs that promote bleeding, or alcohol abuse. The risk of bleeding can range from 1% (0-1 point) to 12.5% (5 points).

Many of the factors that determine the risk of stroke in patients with atrial fibrillation also predict the risk of bleeding, but the former complication is usually more severe than the latter. About 70% of strokes associated with atrial fibrillation are fatal or result in permanent serious neurologic deficit, whereas bleeding is less likely to be fatal and less likely to leave permanent sequelae in survivors. Only when the risk of stroke is low and the risk of bleeding is high (eg, young patients with atrial fibrillation without other risk factors for stroke but with a high risk of major bleeding due to malignancy, a history of bleeding, or a high risk of trauma) does the risk/benefit ratio not favor antithrombotic therapy. In addition, the preferences of the patient with atrial fibrillation are important in decisions about the choice of therapy for thromboembolism prevention.

Warfarinin oral anticoagulants

The usefulness of aspirin in preventing thromboembolism in patients with atrial fibrillation is questionable. In contrast, warfarin is recognized as a highly effective drug for preventing stroke in patients with atrial fibrillation, reducing the risk of this complication by 68% and overall mortality by 26%. However, more than half of the patients who are prescribed warfarin have never taken it, about half of the patients who received this anticoagulant have refused it, and in those who continue treatment, the INR is in the therapeutic range in only about half of the cases. Consequently, only a small minority of patients with atrial fibrillation are adequately treated with warfarin. The degree of increase in INR with a chosen dose of warfarin is unpredictable due to numerous factors affecting the pharmacokinetics and pharmacodynamics of the drug. INR monitoring, often with warfarin dose adjustments, is required at least monthly to ensure that the INR is maintained in the target range of 2.0–3.0. Even with careful monitoring in well-designed studies, the therapeutic INR range is found in about 65% of cases, and the bleeding rate in patients with atrial fibrillation is about 3.0% per year. Several new oral anticoagulants have been developed to avoid some of the problems associated with warfarin. Dabigatran (Pradaxa, Boehringer Ingelheim), rivaroxaban (Xarelto, Bayer), and apixaban (Eliquis, Pfizer/Bristol-Myers Squibb) have been evaluated in large clinical trials and found to be safe and effective.

They exert an anticoagulant effect by reversibly inhibiting thrombin (dabigatran) or factor Xa (rivaroxaban and apixaban). Peak blood concentrations and the anticoagulant effect of these drugs are observed shortly after oral administration. After discontinuation of these anticoagulants, their effect rapidly declines. The recommended doses vary little in individual patients; monitoring of the anticoagulant effect is not required. Dose reduction is indicated in patients with reduced renal function, old age, or low body mass index. All new oral anticoagulants have 2 disadvantages: laboratory monitoring of their anticoagulant effect is difficult, and rapid reversal of their effect is not yet available.

The efficacy and safety of dabigatran have been established in the United States, Canada, and Europe for the prevention of stroke and systemic thromboembolism in patients with atrial fibrillation and atrial flutter. In the RE-LY 18 study, 113 patients with atrial fibrillation (mean CHADS2 score 2.1) were randomized to dabigatran (110 mg or 150 mg twice daily in a double-blind manner) or warfarin (target INR 2.0-3.0) administered in an open-label manner for a mean of 2.0 years. The primary endpoint (stroke or systemic thromboembolism) occurred at a rate of 1.69% per year with warfarin, 1.53% per year with dabigatran 110 mg (relative risk vs. warfarin 0.91; p = 0.34), and 1.11% per year with dabigatran 150 mg (relative risk vs. warfarin 0.66; p < 0.001). The incidence of major bleeding was 3.36% per year in the warfarin group, 2.71% with dabigatran 110 mg (relative risk vs. warfarin 0.8; p = 0.003), and 3.11% with dabigatran 150 mg (relative risk vs. warfarin 0.93; p = 0.31). The overall incidence of stroke, systemic thromboembolism, pulmonary embolism, myocardial infarction, death, or major bleeding was 7.64% per year with warfarin, 7.09% per year with dabigatran 110 mg (relative risk versus warfarin 0.92; p = 0.10), and 6.91% per year with dabigatran 150 mg (relative risk versus warfarin 0.91; p = 0.04). Patients receiving dabigatran had more gastrointestinal bleeding and a two-fold increased likelihood of dyspepsia.

Rivaroxaban is approved in the US, Canada, and Europe for the prevention of stroke and systemic thromboembolism in patients with atrial fibrillation/atrial flutter. In the double-blind ROCKET-AF study, 14,264 patients with atrial fibrillation (mean CHADS2 score 3.5) were randomized to receive rivaroxaban 20 mg once daily (15 mg once daily with creatinine clearance 30-49 mL/min) or warfarin (INR 2.0-3.0), monitoring the results of therapy for a mean of 1.9 years. The primary efficacy endpoint (stroke plus systemic thromboembolism) was 2.2% per year in those treated with warfarin and 1.7% per year with rivaroxaban (relative risk vs warfarin 0.79; p = 0.015). The incidence of major bleeding was 3.4% per year in the warfarin group versus 3.6% in the rivaroxaban group (relative risk 1.04; p = 0.58). There were significantly fewer intracranial but more gastrointestinal bleedings with rivaroxaban therapy. The incidence of myocardial infarction was 1.12% per year with warfarin versus 0.91% per year with rivaroxaban (relative risk 0.81; p = 0.121). The new anticoagulant did not demonstrate overall clinical superiority over warfarin in terms of the sum of all adverse outcomes, as did dabigatran at a dose of 110 mg in RE-LY. Nosebleeds and hematuria were significantly more common in those treated with rivaroxaban.

Apixaban is not yet recommended for stroke prevention in atrial fibrillation. In the double-blind ARISTOTLE 18 trial, 201 patients with atrial fibrillation (mean CHADS2 score 2.1) were randomized to receive apixaban 5 mg twice daily (2.5 mg twice daily in patients 80 years or older, weighing 60 kg or less, plasma creatinine 133 μmol/L or more) or warfarin (INR 2.0-3.0) for a mean of 1.8 years. The incidence of the primary outcome (stroke or systemic thromboembolism) was 1.60% per year in the warfarin group versus 1.27% per year in the apixaban group (relative risk 0.79; p = 0.01). The incidence of major bleeding was 3.09% per year with warfarin versus 2.13% with apixaban (relative risk 0.69; p < 0.001) with a statistically significant reduction in intracranial and gastrointestinal bleeding. The combined incidence of stroke, systemic thromboembolism, major bleeding, and all-cause mortality was 4.11% per year with warfarin versus 3.17% per year with apixaban (relative risk 0.85; p < 0.001), and overall mortality was 3.94% versus 3.52% (relative risk 0.89; p = 0.047), respectively. Myocardial infarction was recorded at a rate of 0.61% per year in those receiving warfarin versus 0.53% per year in those receiving apixaban (relative risk 0.88; p = 0.37). No side effect was more common in patients taking apixaban.

In the double-blind AVERROES study, 5,599 patients with atrial fibrillation (mean CHADS2 score 2.0) who could not be treated with warfarin for various reasons were randomized to apixaban 5 mg twice daily (2.5 mg twice daily in some patients) or aspirin (81-325 mg/day) for a mean of 1.1 years. The study was stopped early due to clear differences in treatment outcome. The incidence of the primary outcome (stroke or systemic thromboembolism) was 3.7% per year in those receiving aspirin versus 1.6% per year in those receiving apixaban (relative risk 0.45; p < 0.001). The incidence of major bleeding was 1.2% per year with acetylsalicylic acid and 1.4% with apixaban (relative risk 1.13; p = 0.57) with no significant differences in the incidence of intracranial or gastrointestinal bleeding.

Another factor Xa inhibitor, edoxaban, is currently being compared with warfarin in a randomized phase III study, ENGAGE AF - TIMI 48, involving more than 20,000 patients with atrial fibrillation.

Thus, apixaban, dabigatran 150 mg, and rivaroxaban are more effective than warfarin in preventing stroke and systemic thromboembolism in patients with atrial fibrillation. Apixaban and dabigatran 110 mg cause less bleeding than warfarin, and dabigatran 150 mg or rivaroxaban - no more than warfarin. Any of the new anticoagulants causes intracranial bleeding significantly less often compared with warfarin.

Elderly patients

Age over 75 years is a risk factor for ischemic stroke and major bleeding. In the RE-LY study, the efficacy of dabigatran 150 mg was not significantly different in patients aged 75 years and over and those aged under 75 years, but the new anticoagulant caused more bleeding in the older age group. Therefore, it is reasonable to prescribe dabigatran 110 mg to patients aged 75 years and over. Rivaroxaban and apixaban demonstrated similar ability to prevent thromboembolism and major bleeding in patients aged 75 years and over and those aged under 75 years. However, it seems reasonable to reduce the dose of any of the new anticoagulants, especially dabigatran, in patients aged 75 years and over and certainly in those aged 80 years and over.

Ischemic heart disease

It is known that treatment with warfarin (INH 1.5 or more) for primary prevention of coronary complications is as effective as the use of acetylsalicylic acid. In secondary prevention after myocardial infarction, monotherapy with warfarin (INH 2.8-4.8) prevents coronary events, as does acetylsalicylic acid. The advantage of a combination of acetylsalicylic acid with clopidogrel in the first year after acute coronary syndrome (with or without percutaneous coronary intervention) has been shown compared to warfarin alone or its combination with acetylsalicylic acid.

There are no dedicated randomized controlled trials of antithrombotic treatment in patients with atrial fibrillation who also have coronary artery disease (CAD). In patients who are simultaneously prescribed oral anticoagulants for stroke prevention and antiplatelet therapy for coronary event prevention, the so-called “triple therapy” (an oral anticoagulant, aspirin, and a thienopyridine derivative), newer oral anticoagulants have not been compared with placebo or aspirin in stable CAD, acute coronary syndromes, or percutaneous coronary intervention. However, in trials comparing newer oral anticoagulants with warfarin in patients with atrial fibrillation, the incidence of coronary events did not differ significantly between the subgroups of patients with CAD.

In the RE-LY study, dabigatran use was associated with a trend toward an increased incidence of myocardial infarction compared with warfarin (relative risk 1.27; p = 0.12), but overall mortality was reduced with the new anticoagulant. In patients with a history of coronary artery disease/myocardial infarction, dabigatran did not increase the combined incidence of myocardial infarction, unstable angina, cardiac arrest, and cardiac death compared with warfarin (relative risk 0.98; p = 0.77), and reduced the incidence of stroke or systemic embolism (relative risk 0.88; p = 0.03). In the ROCKET-AF study, there was a trend toward a decrease in the incidence of myocardial infarction with rivaroxaban, and in the ARISTOTLE project, with apixaban. Available data do not suggest a reduction in stroke prevention interventions in patients with atrial fibrillation receiving treatment for coronary artery disease, nor do they support concerns about a greater risk of coronary events with the use of newer oral anticoagulants compared with warfarin.

In three randomized phase II trials to find the optimal dose of the new anticoagulant in triple therapy versus the combination of aspirin/clopidogrel, a significant increase in the incidence of bleeding was observed with triple therapy. At the same time, no significant differences in the risk of major ischemic coronary events were observed. Patients with coronary artery disease in these trials were younger than participants in modern trials of atrial fibrillation treatment comparing new oral anticoagulants with warfarin and had no clear indications for anticoagulant therapy. The phase III ATLAS ACS 2 - TIMI 51 trial using rivaroxaban in triple therapy versus the combination of aspirin plus clopidogrel revealed a statistically significant reduction in the primary endpoint (the total number of cardiovascular deaths, myocardial infarctions, and strokes), but also a significant increase in the incidence of bleeding in the new anticoagulant group.

A similar phase III study, APPRAISE-2, which used apixaban was stopped early due to a high rate of major bleeding. The risk of bleeding would naturally increase with the addition of any new oral anticoagulant to dual antiplatelet therapy, similar to what is seen with warfarin in “triple therapy.”

In patients with atrial fibrillation/flutter in the setting of stable coronary artery disease, antithrombotic therapy should be selected based on stroke risk (aspirin for most patients with a CHADS2 score of 0 and an oral anticoagulant for most patients with a CHADS2 score of 1 or more). Patients with atrial fibrillation/flutter who have had an acute coronary syndrome and/or undergone percutaneous coronary intervention should receive antithrombotic therapy that is selected based on a balanced assessment of the risk of stroke, recurrent coronary events, and bleeding associated with the use of combination antithrombotic therapy, which in patients at high risk of stroke may include aspirin, clopidogrel, and an oral anticoagulant.

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Limiting the effect of new oral anticoagulants

There are currently no specific drugs that block the effect of new oral anticoagulants. In case of overdose, it is recommended to quickly take an sorbent that will bind the drug in the stomach. Hemodialysis is recommended to remove dabigatran from the blood, but not other oral anticoagulants that bind more actively to plasma proteins. Blood coagulation factors such as prothrombin complex concentrates or activated factor VII are recommended in case of uncontrolled bleeding during treatment with all new oral anticoagulants.

Choices of Oral Anticoagulant

The competition between oral anticoagulants is dynamically unfolding under the close attention of specialists. Conclusions based on indirect comparisons of new drugs with each other may be erroneous, since there are significant differences between the studies. At the same time, direct comparisons of new oral anticoagulants in large randomized studies are not planned. Therefore, it is necessary to take into account the conclusion that each of the three new anticoagulants is significantly more effective than warfarin at any risk of thromboembolism in patients with atrial fibrillation, but their superiority is especially noticeable with a higher number of CHA2DS2-Vasc points. All new oral anticoagulants cause less intracranial hemorrhage compared with warfarin.

Likely candidates for treatment with dabigatran, rivaroxaban or apixaban include patients unwilling to take warfarin, new patients not receiving oral anticoagulants, and those with labile INR while on warfarin. Patients with stable INR on warfarin may be switched to one of the newer agents, but this cannot be the primary goal at present. Self-monitoring of INR at home by patients, which is rapidly gaining popularity in Europe and the USA, is an effective way to maintain the degree of hypocoagulation in the therapeutic range and should lead to better outcomes with warfarin.

When choosing between the currently available dabigatran and rivaroxaban, one should take into account some limitations of the former (problems with use in severe chronic kidney disease, the need to reduce the dose in old age) and a certain convenience of the latter (once-daily administration).

Prof. S. G. Kanorsky. Prevention of thromboembolism in patients with atrial fibrillation: the problem of choosing an oral anticoagulant // International Medical Journal - No. 3 - 2012