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

Atrial fibrillation (AF) is one of the main causes of stroke in the elderly. Its prevalence is 4.5 million people in the countries of the European Union and more than 3 million people in the US with a projected increase in the number of Americans with atrial fibrillation up to 7.5 million by 2050. The frequency of atrial fibrillation increases with age, therefore, in connection with the aging of the population, the severity of the problem of cardioembolic stroke is steadily increasing.

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Prevention of stroke in patients with non-valvular atrial fibrillation and chronic kidney disease

Chronic kidney disease (CKD) is often found in patients with atrial fibrillation and can affect the metabolism of drugs, the frequency of bleeding and strokes. Therefore, the choice of safe and effective therapy for atrial fibrillation requires an accurate assessment of renal function.

The results of randomized trials of stroke prevention / systemic thromboembolism support the use of oral anticoagulants in patients with a glomerular filtration rate of at least 30 ml / min / 1.73 m2. Clinical studies of antiplatelet agents and oral anticoagulants in patients with atrial fibrillation did not include patients with severe renal dysfunction (glomerular filtration rate less than 30 ml / min / 1.73 m2), so the results of treatment of such patients are not available.

A retrospective analysis of 46 cohort studies (n = 41 425) in patients not necessarily with atrial fibrillation who underwent hemodialysis showed an increase in mortality due to warfarin therapy (relative risk 1.27), clopidogrel (relative risk 1.24), and acetylsalicylic acid ( relative risk 1.06).

Patients with atrial fibrillation who receive an oral anticoagulant should at least annually determine the level of creatinine and calculate the rate of glomerular filtration. In chronic kidney disease and glomerular filtration rate of more than 30 ml / min / 1.73 m2, antithrombotic therapy is performed in accordance with the assessment of stroke risk for CHADS2 according to recommendations for patients with atrial fibrillation and normal renal function. At the 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 the preferred drug is warfarin 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. Atrial fibrillation in patients with a glomerular filtration rate of less than 15 ml / min / 1.73 m2 and hemodialysis are not recommended oral anticoagulants and acetylsalicylic acid for the prevention of stroke.

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, other influences on it are exerted by other clinical factors. According to the system of calculating the risk of CHADS2 stroke, patients with atrial fibrillation are assigned 1 point in the presence of chronic heart failure, arterial hypertension, age over 75 years and diabetes, and 2 points - with a stroke or transient ischemic attack in the anamnesis. Each additional score 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 detailed assessment of the risk assessment in patients with low scores were included in 2010 in the recommendations of the European Society of Cardiologists for Atrial Fibrillation in the form of the CHA2DS2-Vasc system. Similar to CHADS2, the new system estimates the age of a patient with atrial fibrillation older than 75 years at 2 points, and additionally gives 1 point for the age of 65-74 years, vascular disease (myocardial infarction, peripheral arterial atherosclerosis, large aortic plaques) and female floor. In the recommendations of the European Society of Cardiology, the use of CHADS2 is intended primarily, and CHA2DS2-Vasc - to clarify the probability of stroke at a low risk (0-1 points for CHADS2).

Risk of bleeding

The effectiveness of antithrombotic therapy for the prevention of ischemic stroke should be balanced with the risk of large bleeding, especially intracerebral, often leading to death. The risk of bleeding depends on the properties of specific antithrombotic drugs and the different characteristics of patients. Hemorrhagic risk will increase with increasing antithrombotic intensity of therapy, sequentially increasing from:

1. acetylsalicylic acid (75-325 mg / day) or clopidogrel (75 mg / day) in monotherapy, further
2. combination 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 to vitamin K antagonists. For the latter, the risk of hemorrhage depends on the magnitude of the international normalized ratio (MHO) during treatment, the quality of monitoring, the duration of treatment (high risk for the first few weeks), and stability eating behavior and taking drugs that can change the activity of therapy. The risk of bleeding is probably higher in general clinical practice than in strictly controlled clinical trials.

The recommendations of the European Society of Cardiologists for Atrial Fibrillation 2010 include the HAS-BLED bleeding risk calculation system. Patients are awarded 1 point for the presence of arterial hypertension, stroke or bleeding in history, labile MHO, elderly (over 65 years), liver or kidney function, use of drugs that promote bleeding, or alcohol abuse. The risk of bleeding can vary from 1% (0-1 points) to 12.5% (5 points).

Many of the factors that determine the risk of stroke in patients with atrial fibrillation simultaneously predict a risk of bleeding, but the first complication is usually worse than the second. About 70% of strokes associated with atrial fibrillation result in death or persistent severe neurologic deficits, while bleeding less likely leads to death and is less likely to have persistent consequences for survivors. Only with a low risk of stroke combined with a high risk of bleeding (for example, in young patients with atrial fibrillation without other risk factors for stroke but with a high risk of major bleeding due to malignant growth, history of bleeding, high risk of injury) the risk / benefit ratio not in favor of antithrombotic therapy. In addition, the preference of a patient with atrial fibrillation is of great importance in deciding on the choice of a therapy for the prevention of thromboembolism.

Warfarinin oral anticoagulants

The usefulness of using acetylsalicylic acid in preventing thromboembolism in patients with atrial fibrillation is questionable. In contrast, warfarin is recognized as a highly effective drug for the prevention of stroke in patients with atrial fibrillation, which reduces the risk of this complication by 68%, and the overall mortality rate by 26%. However, more than half of patients who have been shown warfarin never took it, about half of patients who received this anticoagulant refused it, and in continuing treatment in only about half of cases, MHO is in the therapeutic range. Consequently, only a small minority of patients with atrial fibrillation are adequately treated with warfarin. The degree of increase in MHO chosen by the dose of warfarin is unpredictable due to numerous factors affecting the pharmacokinetics and pharmacodynamics of the drug. The definition of MHO, often with the correction of the dose of warfarin, is required at least monthly to be more likely to maintain this figure in the target range 2.0-3.0. Even with close monitoring in well-organized studies, the therapeutic range of MHO is detected in approximately 65% of cases, and in patients with atrial fibrillation the bleeding rate is about 3.0% per year. Several new oral anticoagulants have been created to avoid some problems associated with the use of warfarin. Dabigatran (Pradaxa, Boehringer Ingelheim), rivaroxaban (Xarelto, Bayer), and apixaban (Eliquis, Pfizer / Bristol-Myers Squibb) were evaluated in large clinical trials and were found to be safe and effective.

They have an anticoagulant effect, reversibly inhibiting thrombin (dabigatran) or factor Ha (rivaroxaban and apixaban). The maximum levels of concentration in the blood and anticoagulant effect of these drugs are observed soon after ingestion. After the abolition of these anticoagulants, their action is rapidly weakened. The recommended doses vary little in individual patients, monitoring of anticoagulant effect is not required. Dose reduction is indicated in patients with reduced renal function, elderly age or with a low body mass index. All new oral anticoagulants have two drawbacks: the laboratory control of their anticoagulant effect is a complex task, the means for rapid elimination of their action are not yet available.

The effectiveness and safety of dabigatran is recognized in the US, Canada and Europe in the prevention of stroke and systemic thromboembolism in patients with atrial fibrillation and atrial flutter. In the RE-LY study, 18 113 patients with atrial fibrillation (mean score of CHADS2-2.1) were randomized to dabigatran (110 mg or 150 mg twice daily by a double-blind method) or warfarin (target level of MHO 2.0- 3.0), which were used by the open method on average 2.0 years. The primary endpoint (stroke or systemic thromboembolism) was recorded at a frequency of 1.69% per year with warfarin, 1.53% per year with dabigatran 110 mg (relative risk against warfarin 0.91, p = 0.34) and 1, 11% per year - dabigatran 150 mg (relative risk against warfarin 0.66, p <0.001). The incidence of major bleeding was 3.36% per year in the warfarin group, 2.71% - dabigatran 110 mg (relative risk against warfarin 0.8, p = 0.003) and 3.11% - dabigatran 150 mg (relative risk against warfarin 0 , 93, p = 0.31). The total incidence of stroke, systemic thromboembolism, pulmonary embolism, myocardial infarction, death or large bleeding was 7.64% per year in warfarin, 7.09% per year - dabigatran 110 mg (relative risk against warfarin 0.92, p = 0.10) and 6.91% per year - dabigatran 150 mg (relative risk against warfarin 0.91, p = 0.04). In patients receiving dabigatran, more bleeding from the gastrointestinal tract was recorded, doubling the 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 a double-blind ROCKET-AF study, 14,264 patients with atrial fibrillation (mean score of CHADS2-3.5) were randomized to receive rivaroxaban at a dose of 20 mg once daily (15 mg once daily with creatinine clearance of 30-49 mL / min) or warfarin (MHO - 2.0-3.0), monitoring the results of therapy on average 1.9 years. The main efficacy index (stroke plus systemic thromboembolism) was 2.2% per year in patients treated with warfarin and 1.7% per year with rivaroxaban (relative risk against 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 of 1.04, p = 0.58). There was significantly less intracranial, but more gastrointestinal bleeding with rivaroxaban therapy. The incidence of myocardial infarction was 1.12% per year when warfarin was taken against 0.91% per year - rivaroxaban (relative risk 0.81; p = 0.121). Overall, the new anticoagulant did not receive a general clinical superiority to warfarin in terms of the sum of all adverse outcomes, like the dabigatran 110 mg dose in RE-LY. Nasal bleeding and hematuria were significantly more common in patients treated with rivaroxaban.

Apixaban is not yet recommended for the prevention of stroke in atrial fibrillation. In a double-blind ARISTOTLE study, 18,201 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 of age and older, with weight 60 kg or less, plasma creatinine 133 μmol / l or more) or warfarin (MHO 2.0-3.0) on average for 1.8 years. The incidence of major outcomes (stroke or systemic thromboembolism) was 1.60% per year in the warfarin group versus 1.27% per year - apixaban (relative risk 0.79; p = 0.01). The incidence of major bleeding was 3.09% per year when treated with warfarin versus 2.13% with apixaban (relative risk of 0.69; p <0.001) with a statistically significant decrease in intracranial and gastrointestinal bleeding. The total incidence of stroke, systemic thromboembolism, major bleeding and death from any cause was 4.11% per year with warfarin versus 3.17% per year - apixaban (relative risk 0.85, p <0.001), and total mortality 3, 94% against 3.52% (relative risk of 0.89, p = 0.047), respectively. Myocardial infarction was recorded at a frequency of 0.61% per year in those receiving warfarin versus 0.53% per year - apixaban (relative risk 0.88; p = 0.37). No side effect was seen more often in patients taking apixaban.

In a double-blind study of AVERROES, 5599 patients with atrial fibrillation (mean CHADS2 score 2.0), who for various reasons could not be assigned warfarin, were randomized to apixaban 5 mg twice daily (2.5 mg twice daily day in individual patients) or with acetylsalicylic acid (81-325 mg / day) on average for 1.1 years. The study was discontinued prematurely because of apparent differences in the results of therapy. The incidence of major outcomes (stroke or systemic thromboembolism) was 3.7% per year in patients receiving acetylsalicylic acid versus 1.6% per year - apixaban (relative risk 0.45, p <0.001). The frequency of major bleeding was 1.2% per year with acetylsalicylic acid and 1.4% of apixaban (relative risk 1.13, p = 0.57) without significant differences in the incidence of intracranial and gastrointestinal bleeding.

A comparison of another factor Xa inhibitor of Edoxaban with warfarin is currently under way in a randomized phase III ENGAGE AF-TIMI 48 study involving more than 20,000 patients with atrial fibrillation.

Thus, apiksaban, dabigatran 150 mg and rivaroxaban more effective than warfarin prevent stroke and systemic thromboembolism in patients with atrial fibrillation. Apixaban and dabigatran at a dose of 110 mg cause less bleeding than warfarin, and dabigatran 150 mg or rivaroxaban is no more than warfarin. Any of the new anticoagulants is much less likely to cause intracranial bleeding compared to warfarin.

Patients of senile age

Age over 75 years is a risk factor for ischemic stroke and large bleeding. In the RE-LY study, the efficacy of dabiga- trane 150 mg in patients aged 75 years and older and under 75 years did not differ significantly, but a new anticoagulant caused more bleeding in the older age group. Therefore, patients over 75 years of age should be prescribed dabigatran in a dose of 110 mg. Rivaroxaban and apixaban showed a similar ability to prevent thromboembolism and cause large bleeding in patients 75 years of age and older, and also under 75 years of age. However, it seems reasonable to reduce the dose of any of the new anticoagulants, especially dabigatran, in patients over 75 years of age and, certainly, over 80 years.

Cardiac ischemia

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

There are no special randomized controlled trials of antithrombotic treatment of patients with atrial fibrillation who also suffer from ischemic heart disease (CHD). In patients who simultaneously showed oral anticoagulants for the prevention of stroke and antiplatelet therapy for the prevention of coronary events, the so-called "triple therapy" (oral anticoagulant, acetylsalicylic acid and thienopyridine derivative), new oral anticoagulants were not compared with placebo or acetylsalicylic acid in stable CHD, acute coronary syndromes or percutaneous coronary intervention. Meanwhile, in studies comparing new oral anticoagulants with warfarin in patients with atrial fibrillation, the incidence of coronary events in subgroups of patients with IHD did not differ significantly.

The use of dabigatran in the RE-LY trial was accompanied by a tendency to increase the incidence of myocardial infarction in comparison with warfarin treatment (relative risk 1.27, p = 0.12), but the overall mortality with new anticoagulant intake decreased. In patients with IHD / myocardial infarction, the dubigatran did not increase the total incidence of myocardial infarction, unstable angina, cardiac arrest, and cardiac death compared with warfarin (relative risk 0.98, p = 0.77), reduced the incidence of stroke or systemic embolism ( relative risk 0.88, p = 0.03). In the study ROCKET-AF there was a tendency to decrease the incidence of myocardial infarction with rivaroxaban, and in the ARISTOTLE project, apixaban. The available information does not imply a reduction in the prevention of stroke in patients with atrial fibrillation receiving IHD treatment, nor do they confirm fears of a greater risk of coronary events with new oral anticoagulants compared with warfarin.

In three randomized phase II trials, a significant increase in the bleeding rate with "triple therapy" was observed in order to find the optimal dose of the new anticoagulant in triple therapy against the combination of acetylsalicylic acid / clopidogrel. There were no significant differences in the risk of major ischemic coronary events. Patients with IHD in these studies were younger than participants in modern studies of atrial fibrillation who compared new oral anticoagulants to warfarin and did not have clear indications for anticoagulant therapy. Phase III study of ATLAS ACS 2-TIMI 51 with rivaroxaban in triple therapy versus combination acetylsalicylic acid plus clopidogrel revealed a statistically significant reduction in the primary endpoint (total number of cardiovascular deaths, myocardial infarctions and strokes), but also a significant increase in frequency bleeding in the new anticoagulant group.

A similar phase III trial of APPRAISE-2, in which apixaban was used, was discontinued prematurely due to the high incidence of large bleeding. The risk of bleeding should naturally increase with the addition of any new oral anticoagulant to double antiplatelet therapy, similar to what is observed with the use of warfarin as part of "triple therapy".

Apparently, in patients with atrial fibrillation / atrial flutter in the presence of stable ischemic heart disease, antithrombotic therapy should be selected taking into account the risk of stroke (acetylsalicylic acid for the majority of patients with 0 points for CHADS2 and oral anticoagulant for the majority of patients with 1 or more CHADS2 scores). Patients with atrial fibrillation / atrial flutter who have suffered acute coronary syndrome and / or underwent percutaneous coronary intervention should receive an antithrombotic treatment that is selected on the basis of a balanced assessment of the risk of stroke, recurrence of coronary events, and bleeding associated with the use of combined antithrombotic therapy, which in patients at high risk of stroke may include acetylsalicylic acid, clopidogrel and oral anticoagulant.

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Limiting the effect of new oral anticoagulants

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

The choice of oral anticoagulant

The competitive struggle between oral anticoagulants is dynamically unfolding under the close attention of specialists. Conclusions on the basis of indirect comparisons of new drugs among themselves may be erroneous, since there are significant differences between the studies. At the same time, direct comparisons of new oral anticoagulants in large randomized trials are not planned. Therefore, one should take into account the conclusion that each of the three new anticoagulants is much more effective than warfarin in any risk of thromboembolism in patients with atrial fibrillation, but their superiority is especially noticeable with a higher score of CHA2DS2-Vasc. All new oral anticoagulants cause less intracranial hemorrhage compared with warfarin.

Probable candidates for treatment with dabigatran, rivaroxaban or apixaban are patients who do not want to take warfarin, new patients who do not receive oral anticoagulants, as well as individuals with labile MHO on the background of warfarin treatment. Patients with stable MHO with warfarin therapy can be transferred to one of the new drugs, but this can not be the main goal at the moment. Self-determination of MHO at home by the patients themselves, rapidly gaining popularity in Europe and the US, is an effective way of maintaining the degree of hypocoagulation in the therapeutic range and should lead to better results of treatment with warfarin.

When choosing between the currently available dabigatran and rivaroxaban, some limitations of the first (the problem of use in severe chronic kidney disease, the need to reduce the dose in old age) and the certain convenience of the second (once a day) should be taken into account.

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