Innovations in anticoagulant therapy to ensure its effectiveness and safety

The importance of blood density readings for varicose veins

Thick blood with varicose veins is a fairly common occurrence. Standing for long periods of time, heavy physical activity, excess weight and pregnancy are the main reasons for the development of varicose veins. Blood cells slow down their circulation; more power is required to liquefy and pump them, which negatively affects the general condition of the blood vessels. After making an accurate diagnosis, the doctor prescribes certain medications that will improve microcirculation and normalize lymph outflow. Medicines also maintain normal hemostasis in the patient’s body, reduce blood clotting and destroy blood clots.

Viscous, thick blood cannot supply all tissues and organs with oxygen and other useful substances in a timely manner. This leads to numbness of the lower extremities, hypoxia and the active development of varicose veins. Platelets sticking to the walls of veins interfere with normal blood flow. To avoid blood clot rupture and death as a result of pulmonary embolism, it is necessary to take drugs to thin blood clots.

The effect of coagulants on the condition of blood vessels in varicose veins

The scientific name for blood thinners is anticoagulants. They do not get rid of the cause of the disease, but effectively relieve symptoms, have a strengthening effect on the walls of blood vessels, and block the progressive development of varicose veins. Any drug from this pharmacological group is taken strictly as prescribed by a phlebologist after a detailed ultrasound diagnosis.

Anticoagulants are indicated for the following diseases:

• Thrombosis of venous vessels;
• Arterial thrombosis;
• Pulmonary embolism;
• Other cardiovascular diseases associated with the formation of blood clots.

The active components of blood thinning drugs can be synthetic or semi-synthetic substances based on natural stimulants. The most effective are diosmin, heparin, troxerutin, rutin, escin and hesperidin. Each of them stabilizes the condition of blood vessels with varicose veins, reduces capillary fragility and prevents the formation of blood clots.

Contraindications for taking anticoagulants and antiplatelet agents

Like any medications, anticoagulants have a number of contraindications that must be carefully studied before starting to take the pills.

• Individual intolerance to the main components of the drug;
• Low blood clotting;
• The presence of open wounds or trophic ulcers;
• Phlebitis and hemorrhagic diabetes;
• 1st trimester of pregnancy;
• Hemophilia.

Blood thinner for varicose veins

Blood thinning is one of the most important tasks in the complex treatment of varicose veins. At the same time, at each stage of the development of the disease, it is worth selecting certain drugs with a higher proportion of the active substance. Blood clots in damaged areas of the veins pose a dangerous threat to the normal nutrition and functioning of vital organs. Therefore, treatment of varicose veins is most effective in the first stages, when vascular damage has not acquired irreversible consequences.

Medicines to thin blood clots have 2 main directions:

• Anticoagulants - prevent the formation of fibrin clots by inhibiting the activity of proteins.
• Antiplatelet agents are drugs that prevent blood cells from sticking to each other.

Also, venotonics should be included in the complex of drug therapy to strengthen the walls of blood vessels, increase their tone and normalize blood flow in the damaged vein.

Anticoagulants

With varicose veins, the viscosity of blood cells is of great importance. The overall course of the disease and possible complications associated with the formation of blood clots will depend on this indicator. After a thorough history taking and ultrasound diagnostics, a phlebologist may prescribe medications that prevent the formation of blood clots - anticoagulants. They come in two types:

• Direct action - neutralizes risk factors for excessive coagulation, helps to dilute blood stagnation. Available in the form of injections or tablets (heparin).
• Indirect action - slowly reduce blood clotting factors, the medicine has a dose-dependent effect, so results can be observed after a course of taking the medicine. Representatives of this group of drugs are Aspirin and Warfarin.

Antiplatelet agents

Medicines in this group are capable of diluting venous fluid in varicose veins, preventing the “gluing” and “sticking” of red blood cells, and improving vascular patency. To prevent and treat the symptoms of thrombophlebitis, the following drugs are most often prescribed:

• Aspirin is a blood-thinning tablet that belongs to the group of non-steroidal anti-inflammatory drugs. Dispensed without a prescription, available in every pharmacy. Aspirin has many contraindications, so it should be taken in small doses under the strict supervision of the attending physician;
• Dipyridamole is a drug that can thin clots and inhibit platelet aggregation. Its pharmacological properties are similar to aspirin, but less dangerous due to contraindications.
• Warfarin is a medication for the treatment and prevention of thrombosis and varicose veins with a wide range of applications. It is a vitamin K antagonist, i.e. interferes with the active action of this vitamin.

Innovations in anticoagulant therapy to ensure its effectiveness and safety

Summary. The Russian National Congress of Cardiologists 2022 was held from September 29 to October 1. Due to the unfavorable epidemiological situation, the congress was held online - 149 meetings in 15 virtual halls. The main advantage of this format is that all recordings of the meetings are uploaded to the YouTube channel of the Russian Society of Cardiology and are available for viewing at any convenient time. At the congress there was a discussion of all issues related to cardiology and its intersections with other specialties. The recently updated 2022 European Society of Cardiology guidelines on the management of atrial fibrillation have been particularly discussed. Over the past 10 years, anticoagulant therapy has gone through a number of major changes. The new recommendations for the use of oral anticoagulants have been well received by both the medical community and patients. Correct comprehensive assessment of risk factors in patients with atrial fibrillation allows one to prescribe adequate therapy, taking into account its effectiveness and safety. The era of direct oral anticoagulants was well represented at satellite symposia, where leading cardiologists, department heads, and heads of large research units spoke.

The Russian National Congress of Cardiology took place some time after the publication of new recommendations of the European Society of Cardiology (ESC) 2022, the provisions of which became the focus of attention of many speakers.

One of the most ambitious tasks of Russian healthcare by 2024 is to reduce mortality rates by almost 25%, including from cardiovascular diseases (CVD). A significant contribution to mortality is made by atrial fibrillation (AF), which is epidemiologically described by such indicators as the prevalence of the disease in the population, the proportion of patients receiving anticoagulant therapy, and its effectiveness.

S. A. Boytsov, General Director of the Federal State Budgetary Institution "National Medical Research Center of Cardiology", one of the main freelance cardiologists at the federal level, points out in his report that in order to increase the effectiveness of CVD treatment, it is necessary to increase the volume of dispensary observation at therapeutic sites, expand benefits, and develop methods for remote monitoring to improve adherence to treatment, monitoring the achievement of target indicators of the cardiovascular system, especially blood pressure, as well as compliance with the requirements of clinical recommendations and quality control.

Over the past 10 years, cardiology, and anticoagulant therapy in particular, has gone through a number of major changes: the era of vitamin K antagonist recommendations has given way to the more preferred direct oral anticoagulants (DOACs). The new recommendations have been well received by both the medical community and patients. The priority positions of DOACs have finally been strengthened, as recorded in the new 2022 ESC recommendations, and even high bleeding risk indicators should not be considered as a reason for refusing DOACs.

The dilemma of preventing thromboembolism and hemorrhagic risks

The eternal dilemma of anticoagulant therapy about reducing the frequency of thromboembolism and increasing the risk of bleeding was commented on by V. Yu. Mareev, MD, Chief Researcher of the International Scientific Research Center, Professor of the Faculty of Physical Medicine of Lomonosov Moscow State University, paraphrasing the famous quote from Gogol’s play “Marriage”: “If I had a medicine that was effective, like warfarin, and safe, like Aspirin, and I didn’t have to follow any diets or rules of administration, and, perhaps, not measure anything, then we would immediately decide. Now go think!”

Can modern pharmacology offer such a drug? Yes, says Vyacheslav Yurievich. A direct inhibitor of coagulation factor Xa, apixaban, has a high safety profile. Compared with Aspirin, for every 1000 patients, apixaban causes only 2 additional bleeding events, and in patients with AF treated for 1 year, it would prevent stroke or systemic embolism in 21, death in 9, and hospitalization for CVD in 33 patients.

Moreover, with regard to hemorrhagic risks, we are talking only about the so-called “nuisance” bleeding (nasal in 68% of cases, gingival in 25% and subcutaneous in 7%) without increasing the risk of major bleeding and stroke. Unfortunately, these events are sometimes an unjustified reason to discontinue apixaban therapy. In this context, it must be remembered that treatment of patients with AF without interruption is accompanied by the occurrence of strokes and systemic embolism only in 1.7% of cases, with a temporary break in treatment - already in 6.2%, and with long-term withdrawal - in 25.6% .

New data in the treatment of comorbid patients with gastrointestinal bleeding

At another symposium, dedicated to numerous aspects of managing patients with AF, V. Yu. Mareev focused on the most complex group of elderly patients with a large number of comorbid conditions in the report “Fragile patient: how not to break?”.

Age is one of the most important risk factors for the development of AF. When all other risk factors are controlled, in people aged 55-95 years, AF occurs in less than a quarter (23.4%) of cases, and in the absence of control of more than 1 risk factor - already in 38.4%.

The number of comorbid conditions directly affects the frequency of hospitalizations. According to a large study from the USA, which included more than 120 thousand patients, more than 80% of hospitalizations were in the comorbid group with 5 or more non-cardiac pathologies. Typically, severely comorbid patients require more aggressive therapy. At the same time, an elderly patient with AF requires equally effective and safe (!) protection against stroke.

The European Society of Cardiology algorithm for the selection of oral anticoagulants in “frail” patients with a high risk of gastrointestinal bleeding (GIB), the presence of chronic kidney disease or chronic renal failure, as well as in elderly and elderly patients leads to a choice between several different DOACs, but of all risk factors, only apixaban can be used at its maximum effective dose of 5 mg. Among all DOACs, the profile characterizing the net clinical benefit when combining thromboembolic complications with all major bleeding and deaths was positive only for apixaban, which gives it every opportunity to “not break” a “fragile” patient.

Zh. D. Kobalava, Professor, Doctor of Medical Sciences, Head of the Department of Internal Medicine and Clinical Pharmacology of the RUDN University, told the symposium audience about the “scissors effect.” In patients with AF, the risk of stroke increases with age, but they are less likely to be prescribed effective medications. However, whether increasing age is associated with an increased risk of embolic or hemorrhagic events requires further evaluation.

To objectify this evaluation of therapy, a net clinical benefit (NCB) metric has been developed, which creates a common denominator for the effectiveness and safety of a drug. Its calculation in major clinical trials of DOACs allows us to conclude that apixaban is the most preferable anticoagulant in certain groups of patients. According to a two-dimensional assessment of the effectiveness and safety of antithrombotic drugs, the majority of new DOACs are in the area of ​​the so-called “ideal drug” in all categories comparing the incidence of thromboembolic complications with major and intracranial bleeding, as well as in comparison with the incidence of deaths. Moreover, among all DOACs, the profile characterizing NCB in the combination of thromboembolic complications with any of the above criteria was positive only for apixaban, including in relation to gastrointestinal tract.

GI bleeding is the most common bleeding associated with anticoagulant therapy, followed by intracranial bleeding (according to a study of rivaroxaban and warfarin by Japanese scientists).

Yuri Mikhailovich Lopatin, Doctor of Medical Sciences, Professor, Head of the Department of the Volgograd State Medical University, Head of the IHD Department of the Volgograd Cardiocenter, in his report focused on the choice of an anticoagulant for the risk of gastrointestinal tract disease.

There are a considerable number of well-studied factors contributing to the development of gastrointestinal tract bleeding, including those associated with anticoagulant therapy, and the term “high risk of gastrointestinal tract bleeding” may not always accurately reflect the current clinical situation. For example, patients with ulcer bleeding associated with H. pylori may no longer be at high risk after eradication of the infection. Among its factors, there are also gender differences: for example, taking rivaroxaban is associated with more frequent gastrointestinal tract infections in men, but no such changes are observed for apixaban.

The incidence of gastrointestinal bleeding in patients taking DOACs is very uneven - the lowest rates of these bleedings are achieved while taking apixaban, relative risk 0.89 [CI 0.70-1.15]. For comparison, for dabigatran 150 mg this figure is 1.49 [CI 1.21-1.84], for rivaroxaban 20 mg it is 1.61 [CI 1.30-1.99]. The position of choosing the safest drug from the point of view of gastrointestinal tract has been reflected in practical recommendations for several years: apixaban in a standard dosage of 5 mg or dabigatran in a reduced dosage of 110 mg has been established as a first-line drug. It is worth noting that apixaban does not require a dosage reduction and maintains its safety profile with maximum therapeutic effectiveness.

Obviously, with active bleeding, it is necessary to stop taking anticoagulants and take specific measures to stop it. However, even under anticoagulation conditions, gastrointestinal tract infections, as a rule, do not lead to deaths and permanent disability, which dictates the need to continue therapy, giving preference to either dabigatran at a reduced dosage or apixaban at a standard effective dose.

Management of patients with atrial fibrillation and acute coronary syndrome

The symposium listeners got acquainted with the results of classical studies concerning double and triple antithrombotic therapy from the reports of Professors D. A. Zateyshchikov, head of the primary vascular department of City Clinical Hospital No. 51 (Moscow), and Peter R. Sinnaeve from the Leuven University Hospital (Belgium). Internal protocols for the management of patients with acute coronary syndrome (ACS) and AF in advanced domestic medical institutions turned out to be consistent with current European recommendations.

It is known that the treatment of these conditions is not interchangeable; on one side of the scale there is always the risk of stent thrombosis and recurrent stroke or heart attack, on the other - the risk of serious bleeding. Available recommendations can often be contradictory and unclear. Fortunately, the DOAC era was marked by a series of seminal studies: PIONEER AF-PCI (rivaroxaban), RE-DUAL PCI (dabigatran etexilate), ENTRUST (edoxaban) and AUGUSTUS PIONEER-PCI (apixaban). The first work with a self-explanatory title was devoted to rivaroxaban. It took the important step of showing that dual therapy was safer than triple therapy, although it used “lower” dosages of rivaroxaban. The largest study with the most unique design is AUGUSTUS. It included 4600 patients, including those with ACS, who did not undergo percutaneous coronary intervention (PCI). The study results reported not only increased bleeding risks with aspirin, but also a safety advantage of apixaban over warfarin.

The main conclusion that can be drawn from all four studies is the superiority of dual therapy over triple therapy, which is also confirmed by the new ESC recommendations. Another conclusion that follows from the AUGUSTUS results concerns the duration of dual therapy - in stable patients after primary coronary intervention, 6 months of dual therapy may be sufficient, after which a transition to DOAC monotherapy is possible.

Use of DOACs in complex clinical cases: expert position

The symposium “How the results of new research help in difficult clinical situations” was held according to an unconventional scenario with an active discussion of real clinical cases.

The first clinical case was presented by Denis Anatolyevich Andreev, Doctor of Medical Sciences, Professor, Head of the Department of Cardiology, Functional and Ultrasound Diagnostics, Director of the Cardiology Clinic of Sechenov University.

The following experts took part in the discussion of the clinical case:

• Oleg Ivanovich Vinogradov, Doctor of Medical Sciences, Head. Department of Neurology with a course of neurosurgery at the National Medical and Surgical Center named after. Pirogov.
• Andrey Leonidovich Komarov, MD, Leading Researcher, Laboratory of Clinical Problems of Atherothrombosis, National Medical Research Center of Cardiology

First clinical case. A 78-year-old female patient was admitted to the department with a diagnosis of ST-segment elevation ACS. The patient had a history of long-term arterial hypertension, AF without taking anticoagulants with hemorrhagic stroke requiring surgical intervention.

The patient was given Aspirin by ambulance. The first question that the experts discussed concerned further management tactics - invasive or conservative? It was decided to perform coronary angiography with installation of a bare metal stent in the affected right coronary artery, and aspirin and clopidogrel were prescribed.

During hospitalization, type 2 diabetes mellitus and a glomerular filtration rate of 38 ml/min/1.73 m2 were detected. Stratification of hemorrhagic risks according to the CHA2DS2-VASc scale – 6 points, according to the HAS-BLED scale – 5 points. Is anticoagulant therapy indicated in this case? The experts concluded that a high bleeding risk does not influence the choice of anticoagulants for stroke prevention, which is consistent with the new European ESC recommendations. What do practicing neurologists think about this? O. I. Vinogradov expressed the opinion that the prescription of anticoagulants after a hemorrhagic stroke is permissible for 2-4 weeks, depending on the nature of the neurological lesion.

Next, the question arose about the treatment regimen. According to the ESC-2020 recommendations, triple therapy with aspirin discontinuation after 1 week is recommended for most patients with ACS and AF undergoing PCI. The experts reviewed a wide range of triple therapy options. The combination “warfarin + clopidogrel + Aspirin” was considered the least preferable. Making a clinical decision to prescribe rivaroxaban was difficult due to differences in doses specified in the ESC-2020 clinical recommendations and the instructions for medical use of the drug. Dabigatran, according to the 2020 ESC recommendations, at a dosage of 110 mg demonstrated, although not statistically significant, a slightly greater risk of heart attack. As a result, the experts came to the conclusion that the combination “apixaban 5 mg/day + clopidogrel” is the most optimal both in terms of the dosage used and the “efficacy/safety” ratio.

The next clinical case was presented by A.L. Komarov.

Igor Anatolyevich Zolotukhin, MD, Head, also joined the discussion regarding the “little things” in the treatment of thrombosis in patients with cancer pathology. Department of Fundamental and Applied Research in Surgery, Russian National Research Medical University named after. Pirogov.

Second clinical case. The patient, 21 years old, was admitted with submassive pulmonary embolism (PE), ascending thrombosis of the inferior vena cava to the level of the renal veins and right ventricular overload. She was in the postoperative period after a cesarean section (1.5 months ago). Over the past months, she has complained of headaches, a syncopal episode and convulsions before childbirth. An MRI revealed a massive brain tumor with occlusive triventricular hydrocephalus.

How to treat the prescription of anticoagulants to patients with venous thromboembolic complications (VTEC) in the presence of tumors of the central nervous system? In such situations, there are no clear-cut solutions, but all experts agreed that in the absence of other contraindications, anticoagulant therapy is indicated in this case. This opinion is confirmed by a number of studies that included apixaban. The 2022 Lancet Oncology consensus on the treatment and prevention of VTEC in patients with cancer suggests that the use of DOACs or low molecular weight heparins (LMWH) for proven PE in patients with brain tumors is acceptable, but not in the case of upcoming neurosurgical treatment.

Venous thromboembolism from the perspective of a multidisciplinary approach

During the symposium “VTE: what’s new in treatment and prevention?” representatives of various medical specialties (cardiology, anesthesiology-reanimatology, phlebology) assessed the effect of DOACs on the management of patients with VTEC, including in complex clinical situations associated with cancer or the need for surgical interventions. Despite its “youth”, this group of drugs is actively occupying new niches in the treatment of AF and thromboembolic conditions.

Chairman of the symposium “VTE: what’s new in treatment and prevention?” was E. P. Panchenko, MD, professor, head of the department of clinical problems of atherothrombosis of the National Medical Research Center of Cardiology. She also presented a comprehensive report on the problems of cancer-associated thrombosis and their solutions.

Venous thromboembolic complications and cancer are closely related. Thus, in the structure of causes of death in cancer patients, after obvious progression of the underlying disease, pulmonary embolism takes second place, accounting for 9% of deaths. According to the large Garfield registry, more than half (54%) of patients with VTEC have cancer as the underlying cause of thrombosis. In addition to the oncological disease itself, these patients are most often characterized by old age, comorbid conditions, surgical interventions or a history of specific antitumor therapy. The most thrombogenic are cancers of the pancreas, stomach, lungs, ovary, bladder, and colorectal cancer.

Anticoagulant therapy for such patients is specific. Studies examining the efficacy and safety of DOACs in subgroups of patients with cancer have shown that these drugs are at least as good as warfarin in preventing recurrent venous thrombosis. Although LMWH remains the gold standard for the treatment of cancer-associated thrombosis, the professional medical community is actively monitoring the results of specialized studies comparing DOACs and LMWH in cancer patients. According to recent studies (ADAM, EHS, 2022) comparing apixaban with dalteparin sodium, the oral anticoagulant demonstrated a lower rate of recurrence of VTE - 3.4% versus 14.1%, respectively, while none were recorded in this study major bleeding.

In the largest study to date, CARAVAGGIO, studying DOACs in the treatment of VTEC in cancer patients, the goal was to prove that apixaban copes with its task no worse than dalteparin. Efficacy endpoints included recurrence of deep vein thrombosis (DVT) or PE, and safety was assessed by major bleeding. After patients were randomized, treatment continued for 6 months with an additional follow-up period of 1 month. Statistically robust data confirmed that apixaban was noninferior to dalteparin in preventing recurrent VTE, particularly in recurrent PE, and demonstrated similar performance on primary safety endpoints.

Issues of long-term anticoagulant therapy for VTEC were covered in the report of Igor Semenovich Yavelov, MD, head of the department of fundamental and clinical problems of thrombosis in non-infectious diseases of the National Medical Research Center for Therapy and Preventive Medicine.

The modern regimen for the use of anticoagulants in patients with DVT and/or PE involves the use of high (therapeutic) doses of anticoagulants for at least 3 months. Then a decision must be made on the need to extend therapy, taking into account the characteristics of the individual patient. In particular, for distal DVT of the lower extremities, further use of anticoagulants is not required. Proximal DVT of the lower extremities, like PE, is more prone to relapse and requires a balanced medical decision.

This decision may be helped by the updated 2022 European Society of Cardiology PE guidelines, which divide the risk of recurrence into 3 groups: low, medium and high. The most favorable situation is in which the leading risk factor for pulmonary embolism acts very strongly and is subsequently eliminated (surgical intervention, acute non-surgical disease) - then both European and American colleagues recommend 3 months of anticoagulant therapy. At the other end of the spectrum are patients with a continued high risk of relapse, which may be due to existing malignancies, antiphospholipid syndrome, or recurrent episodes of DVT and/or PE. In this case, the formulation of the duration of therapy sounds like “indefinitely.” The intermediate-risk category includes the most heterogeneous group of patients, in which the duration of treatment is also often uncertain, but in any case we are talking about years rather than months. When it is safe to stop anticoagulants in such patients is a question to which experts do not yet have an exact answer.

The extremely important topic of rules for taking anticoagulants during operations and traumatic procedures was presented by Mikhail Nikolaevich Zamyatin, Doctor of Medical Sciences, Professor, Honored Doctor of the Russian Federation, Head of the Department of Anesthesiology and Reanimatology of the National Medical Center named after. N.I. Pirogova.

It is obvious that taking anticoagulants disrupts the hemostatic system and, as a result, increases the risk of blood loss and the need for transfusions, however, from the position of an anesthesiologist, these situations are controllable and do not affect mortality. On the other hand, drug withdrawal significantly increases the risk of myocardial infarction and it is believed that 2/3 of all sudden cardiac complications in the perioperative period are associated with the withdrawal of anticoagulants or antithrombotics.

The big problem is that drug withdrawal involves all doctors caring for the patient in the perioperative period, even with relatively minor interventions, for example, in dentistry. Of no less consequence is the fact that many doctors discontinue DOACs using regimens similar to those for warfarin, despite the fundamental difference in the pharmacokinetics of these drugs.

What should include a safety assessment when performing surgery on anticoagulants? First of all, the possibility and feasibility of its implementation in this situation, as well as an assessment of the risk of developing VTEC and bleeding. You need to know that the maximum risk of relapse (50%) upon cessation of treatment remains for 3-4 weeks after VTEC; treatment for a month reduces the risk of relapse to 8-10%, and within 3 months - to 4-5%.

If surgery can be delayed and await the recommended dose reduction of the anticoagulant, this will also reduce the risk of bleeding complications. After just 6 months, the cumulative incidence of bleeding complications with apixaban approaches the placebo level. If surgical intervention cannot be postponed, it is necessary to evaluate the need to interrupt the course of anticoagulants and, if necessary, therapy with a heparin “bridge” (when, with what drug and in what dose), but with the awareness of the fact that any transition from one anticoagulant to another is always increases risks.

Conclusion

Despite many unexplored issues, important changes are taking place in cardiology, based on clear and progressive steps and carried out within the framework of evidence-based medicine. There is no doubt about the validity of the findings of the new 2020 ECS guidelines, which highlight the innovative role of DOACs in providing both effective and safe anticoagulant therapy.

The article was published with the support of. The article may express the position of the author, which may differ from the position of the author.

See brief information on the drug apixaban on the 2nd cover.

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V. Tindalsky

Magazine “Treating Doctor”, Moscow, Russia

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Innovations of anticoagulant therapy in ensuring its effectiveness and safety / V. Tindalsky For citation: Tindalsky V. Innovations in anticoagulant therapy in ensuring its effectiveness and safety // Treating Physician. 2020; vol. 23 (11), 60-63. Tags: Congress of Cardiologists, atrial fibrillation, safety of therapy