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“High cholesterol” does not hurt, but it can lead to the development of atherosclerosis. Atherosclerosis affects the cardiovascular system, leading to the formation of atherosclerotic plaques and blood supply disorders. This often ends in heart attacks and strokes.

Today there are many drugs from the statin group. They have been shown to be effective in reducing mortality from cardiovascular disease, but debate continues about their safety. To achieve and maintain the desired levels of lipid metabolism, long-term use of drugs is required, but many patients do not follow the recommendations, causing the effectiveness of treatment to sharply decrease. What to say about patients when doctors have different opinions on this matter.

What are statins

Statins are a group of lipid-lowering drugs. They slow down the work of one of the main enzymes involved in the synthesis of cholesterol - HMC-CoA reductase. This leads to a decrease in cholesterol synthesis in the liver.

A decrease in cholesterol synthesis in hepatocytes increases the number of receptors for low-density lipoproteins (LDL-C) and their subsequent uptake from the bloodstream. In addition, there may be some reduction in the formation of LDL due to inhibition of the synthesis in the liver of their precursor, very low density lipoproteins (VLDL). Thus, statins help reduce total cholesterol, LDL cholesterol and VLDL cholesterol in the blood plasma. At the same time, drugs in this group can reduce the level of TG and slightly increase the level of “good cholesterol” (high-density lipoproteins). The effectiveness of lowering blood cholesterol levels depends on the dose of the drug. To obtain the desired level of reduction, fairly high doses are required.

Their numerous additional properties also contribute to the benefit of statins:

• improving the functional activity of the endothelium;
• stabilization of atheroma (atherosclerotic plaque);
• anti-inflammatory, immunomodulatory and antithrombotic effects;
• positive effect on bone metabolism.

Effect of the drug

The active component in the drug, micronized rivaroxaban, reduces the synthesis of factor Xa, which affects blood clotting. This helps prevent the formation of a blood clot.

Clinical studies have proven the high effectiveness of Xarelto. The active substance in the drug has a stable preventive effect against venous thrombosis and pulmonary embolism. In practice, successful results have also been confirmed when using the drug in the complex treatment of these pathologies. Experts note the drug’s ability to prevent thromboembolic complications in atrial fibrillation, which is characterized by the presence of severe disturbances in heart rhythms.

Rivaroxaban has a rapid, targeted effect. After administration, a stable, predictable dose-dependent response is guaranteed. To achieve the maximum concentration of the active substance in the blood, a couple of hours is enough. During treatment, it is not necessary to monitor coagulation parameters. There are also no dietary restrictions. There is no need to adjust the dosage of the drug depending on the age or body weight of the patient.

Indications

Drugs in this group are prescribed only by a doctor and he selects which active ingredient is suitable and its dosage. Usually, for this purpose, the risk of cardiovascular events is determined using a special scale, questionnaire, and tests are taken to determine the lipid spectrum and biochemical blood parameters. Today, statins are prescribed not only after heart attacks and strokes as secondary prevention. Under certain high-risk conditions, a doctor may use statins in the primary prevention of cardiovascular disease.

Composition and release form

The drug Xarelto is produced in tablet form by the German company Bayer AG. The active substance is micronized rivaroxaban. It can be contained in tablets in quantities of 10, 15, 20 mg

Round biconvex tablets. They are covered with a film shell. Additional components are used in the production of the medicine. You can get acquainted with their list by studying the instructions for use. A distinctive feature of the tablets is the presence of engraving on both sides. This is a triangle indicating the dosage and a brand name in the form of a cross.

Minuses

But there are also unresolved issues in statin treatment. Thus, from 40 to 75% of patients stop taking statins within 1-2 years after starting treatment. Patients name the reasons for this: fear of developing undesirable effects from the instructions for the drug (46%), disbelief that the medicine prolongs life (29.4%), taking a large number of other pills (27.6%), forgetfulness (26.5 %), poor control of blood cholesterol levels while taking medication (18.8%), drug withdrawal by a non-attending physician (13.5%). At the same time, the actual development of undesirable effects on statin therapy was observed only in 11.7% of patients, and their manifestations were mild and moderate in severity.

Muscle symptoms

The incidence of symptoms of muscle damage is 7-29%, according to various sources. These include:

• muscle pain;
• muscle weakness;
• muscle inflammation, determined based on examination of a sample of muscle tissue and/or magnetic resonance imaging (MRI);
• myonecrosis - muscle damage, determined by a significant increase in serum creatine kinase (CK) levels;
• rhabdomyolysis - destruction of muscle tissue with acute kidney damage with an increase in serum creatinine;
• autoimmune myopathy is a rare complication accompanied by severe muscle damage even after discontinuation of the drug;

The reasons for this are not well understood. According to one version, there is a decrease in coenzyme Q10 in muscle tissue and a decrease in the level of vitamin D. The work of mitochondria is affected.

Muscle symptoms occur in 7-29%.

Symptoms usually appear in both arms or legs. The period of appearance is about 4-6 weeks after starting to take statins. Sometimes, with diseases of the joints and ligaments, pain increases. This may be due to muscle weakness. Unusually, physically active people are more likely to suffer from muscle symptoms. One study found that athletes were less tolerant of lipid-lowering therapy.

According to research, these symptoms are rare. But the studies themselves often exclude older patients, those with impaired liver and kidney function, and those taking certain medications, that is, it cannot be said that this is an ordinary elderly person with a “bouquet of diseases.”

Diabetes mellitus and insulin resistance

It has been established that long-term use of statins under certain factors can contribute to the development of insulin resistance and diabetes mellitus. This is evidenced not only by research data, but also by national recommendations of some countries.

Risk factors for developing diabetes when taking lipid-lowering drugs may include:

• high body mass index (BMI);
• elderly age;
• heart failure;
• myocardial infarction in the last six months and high cardiovascular risk;
• family predisposition to type 2 diabetes;
• Asian race;
• smoking, alcohol abuse.

Effects on the liver

When taking statins to reduce the negative effect on the liver, you must avoid taking:

• alcohol;
• drugs that are metabolized in the liver along the same pathways (for example, amiodarone, sulfonamides, methyldopa, cyclosporine).

Statins can negatively affect a damaged liver.

They should not be prescribed for active viral hepatitis until liver parameters return to normal.

Drug interactions

Statins have multiple effects. This is due to the fact that they do not act in isolation, but affect many chemical reactions in the body. This is especially important in patients taking multiple medications for cardiovascular diseases.

Rules of application

Xarelto tablets are intended for internal use. The product can be taken at any time without relying on food intake. If you cannot swallow the tablet, you can crush it. I mix the resulting powder with water or any liquid food. This mixture, if necessary, can be introduced into the stomach using a tube.

Xarelto 10 g, instructions for use indicate this; to prevent pathologies, take 1 tablet once a day. The dosage can be increased if recommended by a doctor.

Therapy is carried out over 2-5 weeks. The course of treatment is prescribed individually depending on the patient’s condition and the complexity of the severity of the pathological condition.

Instructions for use XARELTO® 10 mg

Mechanism of action

Rivaroxaban is a highly selective direct factor Xa inhibitor with high oral bioavailability.

Activation of factor X to form factor Xa (FXa) through the intrinsic and extrinsic pathways plays a central role in the blood coagulation cascade. FXa directly converts prothrombin to thrombin through the prothrombinase complex, and this reaction ultimately leads to fibrin clot formation and platelet activation through thrombin. One FXa molecule is capable of generating more than 1000 thrombin molecules due to the amplification nature of the coagulation cascade. In addition, the reaction rate of factor Xa bound to prothrombinase is increased 300,000 times that of free FXa, causing an explosive increase in thrombin generation. Selective FXa inhibitors are able to stop the increased increase in thrombin generation. As a consequence, rivaroxaban interferes with some specific and general coagulation tests. In humans, dose-dependent inhibition of factor Xa activity was observed.

Pharmacodynamic effects

Studies in humans have shown a dose-dependent inhibition of factor Xa activity. Xarelto® has a dose-dependent effect on prothrombin time and correlates closely with plasma concentrations (r=0.98) when the Neoplastin® kit is used for analysis. Results will vary if other reagents are used. Prothrombin time (PT) should be measured in seconds because the international normalized ratio is calibrated and validated only for coumarins and cannot be used for other anticoagulants. In patients undergoing major orthopedic surgery, the 5/95th percentile for PTT (Neoplastin®) 2 to 4 hours after tablet dosing (i.e., at the time of maximum effect) ranged from 13 to 25 seconds. Clinicopharmacological The study assessed the reversibility of the pharmacodynamics of rivaroxaban under the influence of two different types of prothrombin complex concentrate (PCC). The effects of single doses (50 IU/kg) of 3-factor PCC (factors II, IX and X) and 4-factor PCC (factors II, VII, IX and X) were studied in healthy adult volunteers (n=22). The 3-factor PTC resulted in a reduction in mean Neoplastin® PTT values ​​of approximately 1.0 seconds over 30 minutes compared with the approximately 3.5 second reduction observed with the 4-factor PTC. In contrast, 3-factor PCC had a greater and more rapid overall effect on reversing changes in endogenous thrombin generation than did 4-factor PCC (see Overdose section).

Also, rivaroxaban dose-dependently increases activated partial thromboplastin time (aPTT) and HepTest® result; however, these parameters are not recommended for assessing the pharmacodynamic effects of rivaroxaban. Rivaroxaban also affects anti-factor Xa activity, but there are no standards for calibration.

During standard clinical treatment using Xarelto® there is no need to monitor blood coagulation parameters.

Clinical efficacy and safety

Prevention of venous thromboembolism (VTE) in adult patients with elective hip or knee replacement

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The clinical trial program for rivaroxaban was designed to demonstrate the effectiveness of Xarelto® in preventing cases of venous thromboembolism (VTE), i.e. proximal and distal deep vein thrombosis (DVT) and pulmonary embolism (PE), in patients undergoing major orthopedic surgery lower extremities. More than 9,500 patients (7,050 total hip arthroplasty, 2,531 total knee arthroplasty) participated in the controlled, randomized, double-blind Phase III clinical trials of the RECORD program.

A comparison was made between Xarelto 10 mg once daily, started no earlier than 6 hours after surgery, and enoxaparin 40 mg once daily, started 12 hours before surgery.

In three phase III studies (see Table 1), rivaroxaban significantly reduced the incidence of all VTE (any venographically detected or symptomatic DVT, nonfatal PE, or death) and severe VTE (proximal DVT, nonfatal PE, and VTE-related death). which are prespecified primary and key secondary efficacy endpoints. In addition, in all three studies, the incidence of symptomatic VTE (symptomatic DVT, nonfatal PE, VTE-related death) was lower among patients receiving Xarelto than among patients receiving enoxaparin.

The primary safety endpoint, major bleeding, showed comparable rates in patients receiving Xarelto® 10 mg compared with patients receiving enoxaparin 40 mg.

Table 1: Efficacy and safety results obtained in phase III clinical studies

Pooled analysis of phase III trial results reinforces data from individual studies for reductions in total VTE events, significant VTE events, and symptomatic VTE events with Xarelto 10 mg once daily compared with enoxaparin 40 mg once daily .

In addition to the phase III RECORD study program, a post-marketing, non-interventional, open-label cohort study (XAMOS) was conducted in 17,413 patients undergoing major orthopedic hip or knee surgery to compare rivaroxaban with another standard pharmacological thrombosis prophylaxis in a real-world setting. practices. Symptomatic VTE events occurred in 57 (0.6%) patients in the rivaroxaban group (n=8778) and 88 (1.0%) patients in the standard-of-care group (n=8635; RR 0.63; 95% CI 0.43-0.91); safety study population). Major bleeding was observed in 35 (0.4%) and 29 (0.3%) patients in the rivaroxaban and standard treatment groups (RR 1.10; 95% CI 0.67-1.80). This non-interventional study confirmed the efficacy and safety results observed in the RECORD program.

A retrospective subanalysis of the post-marketing, non-interventional, open-label, cohort study (XAMOS) included 790 patients undergoing surgery for lower extremity fracture and receiving rivaroxaban or other standard pharmacological treatment for thrombosis prophylaxis. Symptomatic VTE events occurred in 2 (0.6%) patients in the rivaroxaban group (n=350) and 5 (1.1%) patients in the standard-of-care group (n=440; RR 0.51; 95% CI 0.10-2.61; safety population). Major bleeding was observed in 1 (0.3%) and 2 (0.5%) patients in the rivaroxaban and standard treatment groups, respectively (RR 0.97; 95% CI 0.06-15.53). In this subanalysis, the incidence of VTE and major bleeding among patients undergoing surgery for lower extremity fractures is comparable to the incidence observed in the RECORD program among patients undergoing elective hip or knee arthroplasty.

Treatment of deep vein thrombosis (DVT) and pulmonary embolism (PE), as well as prevention of recurrent DVT and PE in adults

The Xarelto® EINSTEIN clinical trial program was designed to demonstrate the effectiveness of Xarelto® in the initial and continued treatment of acute DVT and PE, and in the prevention of recurrent DVT and PE.

Treatment in the EINSTEIN program studies lasted up to 21 months. The cumulative incidence of symptomatic recurrence of venous thromboembolism (DVT and/or PE) and major bleeding (cumulative clinical benefit) was statistically significantly lower in the rivaroxaban treatment group than in the comparison group (low molecular weight heparin + VKA); In addition, in the rivaroxaban group, the incidence of major bleeding was 2 times lower than in the comparison group. With prolonged treatment, rivaroxaban was more effective than placebo in terms of the main efficacy indicator, namely, the recurrence rate of VTE with rivaroxaban was 1.3%, with placebo – 7.1%. The incidence of major bleeding was comparable in the rivaroxaban and placebo groups.

In the Einstein Choice study (see table), Xarelto 20 and 10 mg were more effective on the primary endpoint than acetylsalicylic acid 100 mg. The incidence of the primary safety endpoint (major bleeding) was similar in patients treated with Xarelto 20 and 10 mg once daily compared with acetylsalicylic acid 100 mg.

Efficacy and safety results from the phase III Einstein Choice study

*p<0.001 (superiority) Xarelto® 20 mg daily compared with acetylsalicylic acid 100 mg daily; OR=0.34 (0.20–0.59)

**p<0.001 (superiority) Xarelto® 10 mg daily compared with acetylsalicylic acid 100 mg daily; OR=0.26 (0.14–0.47)

+ Xarelto® 20 mg daily compared to acetylsalicylic acid 100 mg daily; RR=0.44 (0.27–0.71), p=0.0009 (nominal) ++ Xarelto® 10 mg daily vs acetylsalicylic acid 100 mg daily; RR=0.32 (0.18–0.55), p<0.0001 (nominal).

In addition to the phase III EINSTEIN studies, a prospective, non-interventional, open-label cohort study (XALIA) was conducted with central assessment of outcomes including venous thromboembolism, major bleeding and death. 5142 patients with acute DVT participated in a study of the long-term safety of rivaroxaban compared with existing anticoagulant therapy in clinical practice. With rivaroxaban, the rates of major bleeding, recurrent venous thromboembolism, and all-cause mortality were 0.7%, 1.4%, and 0.5%, respectively. The adjusted hazard ratios for major bleeding, recurrent venous thromboembolism, and all-cause mortality comparing rivaroxaban with existing therapy were 0.77 (95% CI 0.40 to 1.50), 0.91 (95% CI 0.54 to 1.54), and 0.51 (95% CI 0.24 to 1.07) , respectively. These real-world clinical results are consistent with the established safety profile observed in the phase III EINSTEIN DVT study.

Patients with triple positive antiphospholipid syndrome and a high risk of thromboembolic events

In an investigator-sponsored, randomized, open-label, multicenter, endpoint-blinded study, rivaroxaban was compared with warfarin in patients with a history of thrombosis, a diagnosis of antiphospholipid syndrome, and a high risk of thromboembolic complications (triple positive antiphospholipid syndrome, i.e., presence of lupus anticoagulant, antibodies to cardiolipin and antibodies to beta-2-glycoprotein I)). The study was terminated early after enrollment of 120 patients due to an increase in thromboembolic events in the rivaroxaban group. The mean follow-up period was 569 days. Fifty-nine patients were randomized to rivaroxaban 20 mg (15 mg for patients with creatinine clearance (CrCl) <50 mg/min) and 61 patients were randomized to warfarin (INR 2.0–3.0). Thromboembolic events occurred in 12% of patients randomized to rivaroxaban (4 cases of ischemic stroke and 3 cases of myocardial infarction). No thromboembolic events were observed in patients randomized to warfarin. Major bleeding occurred in 4 patients (7%) in the rivaroxaban group and in 2 patients (3%) in the warfarin group.

Pediatric population

The European Medicines Agency has deferred the obligation to provide results from studies of the treatment of thromboembolic events with Xarelto® in one or more subgroups of children.

The European Medicines Agency has waived the obligation to provide results from studies of the prevention of thromboembolic events with Xarelto® in all groups of children (see information on use in children under Dosage Regimen).