Cardiovascular risk of etoricoxib in rheumatology - an unanswered question

Introduction

Nonsteroidal anti-inflammatory drugs (NSAIDs) are the most commonly used drugs, due to their unique effects - analgesic, anti-inflammatory, antipyretic, etc. [1–2].
NSAIDs have a positive effect on the structural remodeling of the musculoskeletal system in arthritis [3], and are used in the treatment of tumors and proliferative diseases, uveitis, and diseases of the central nervous system (CNS) [4, 5]. It is natural that the demand for drugs is determined by increased attention to their safety. However, studying the safety of NSAIDs is challenging. Difficulties in studying the safety of NSAIDs are determined by a number of objective reasons, one of which is the diversity of NSAID molecules presented in the Russian Federation [1, 2]. Each of the NSAID molecules, due to the physicochemical structural features, has its own COX-dependent and COX-independent properties [1]. Therefore, class-dependent and class-independent side effects of different NSAIDs are expressed to varying degrees [1, 2]. Another difficulty in studying the risks associated with the use of NSAIDs is the variety of indications for their use, which makes the population of patients taking NSAIDs extremely heterogeneous. It is obvious that in patients of different age groups, suffering from different diseases, taking different NSAIDs in different doses for different durations, the safety profile of therapy will vary, and the approaches to determining safety should also be different. Therefore, it is extremely difficult and, most likely, impossible to develop general recommendations for the safe use of NSAIDs. However, studying the safety of NSAIDs is very important, especially with the recognition of the role of NSAIDs as pathogenetically based drugs in the treatment of a number of rheumatic diseases [1–3].

Target

This work is a review of the literature data on the cardiovascular safety of etoricoxib in patients with rheumatoid arthritis, osteoarthritis and ankylosing spondylitis.

Contraindications to the use of Arcoxia

- complete or incomplete combination of bronchial asthma, recurrent nasal polyposis or paranasal sinuses and intolerance to acetylsalicylic acid and other NSAIDs (including a history);

- erosive and ulcerative changes in the mucous membrane of the stomach or duodenum, active gastrointestinal bleeding, cerebrovascular or other bleeding;

- inflammatory bowel diseases (Crohn's disease, ulcerative colitis) in the acute phase;

- hemophilia and other bleeding disorders;

— severe heart failure (II-IV functional classes according to the NYHA classification);

- severe liver failure (more than 9 points on the Child-Pugh scale) or active liver disease;

- severe renal failure (creatinine clearance less than 30 ml/min), progressive kidney disease, confirmed hyperkalemia;

— the period after coronary artery bypass grafting; peripheral arterial diseases, cerebrovascular diseases, clinically significant ischemic heart disease;

- persistent blood pressure values ​​exceeding 140/90 mm Hg. Art. with uncontrolled arterial hypertension;

- pregnancy;

- lactation period (breastfeeding);

- children under 16 years of age;

- hypersensitivity to any component of the drug.

The drug should be used with caution in the presence of anamnestic data on the development of ulcerative lesions of the gastrointestinal tract, Helicobacter pylori infection, in the elderly, in patients who have used NSAIDs for a long time, frequently drinking alcohol, with severe somatic diseases, dyslipidemia/hyperlipidemia, with diabetes mellitus, arterial hypertension, edema and fluid retention, smoking, in patients with CC less than 60 ml/min, with concomitant therapy with the following drugs: anticoagulants (for example, warfarin), antiplatelet agents (for example, acetylsalicylic acid, clopidogrel), corticosteroids (for example, prednisolone), selective inhibitors serotonin reuptake (for example, citalopram, fluoxetine, paroxetine, sertraline).

Literature search strategy

We performed a literature search in open medical citation databases PUBMED, MEDLINE, E-library until 09/01/2019. The search words used were: “cardiovascular risk”, “cardiovascular risk”, “coxibs”, “etoricoxib”, “rheumatoid arthritis”, “osteoarthritis”, “ankylosing spondylitis” in Russian and English.

Articles were excluded if they did not have a full version in Russian or English, did not mention rheumatoid arthritis, osteoarthritis or ankylosing spondylitis as indications for the use of etoricoxib, as well as with unclear criteria for assessing cardiovascular risk or cardiovascular events.

Research results

A total of 210 references were received, of which 16 articles were analyzed according to the selection criteria, including 3 meta-analyses and 1 national register (Table 1).

The results of meta-analyses are conflicting: in two meta-analyses (De Vecchis et al., 2014 and CP Cannon et al., 2006), etoricoxib demonstrated safety equal to placebo and/or other NSAIDs, including diclofenac sodium and naproxen, in terms of the risk of atherothrombotic events [6 –7]; another meta-analysis (S. Trelle et al., 2011) showed an increased risk of cardiac death with etoricoxib compared to placebo and naproxen [8]. Interestingly, despite an increase in cardiac mortality, an increase in the risk of individual cardiovascular events was not found in this meta-analysis. It should be noted that in the meta-analysis by S. Trelle et al. (2011) in addition to patients with rheumatic diseases included patients with colon cancer, prostate cancer, hereditary adenomatous polyposis of the intestine, Alzheimer's disease, i.e., individuals with conditions in which the risk of cardiovascular events and adverse events can be significantly modified by cause of the underlying disease. It is for patients with non-rheumatic diseases associated with an increased risk of cardiovascular events that this work demonstrated high cardiovascular mortality compared with this indicator for patients with rheumatic diseases [8, 9–13]. Interestingly, none of the published meta-analyses analyzed the incidence of comorbid conditions and their treatment [6–9]. Therapy for the underlying disease was also not analyzed [6–9]. This seems to be an important drawback, since the combined use of NSAIDs with glucocorticoids, angiotensin-converting enzyme inhibitors, antiplatelet agents, anticoagulants and/or disease-modifying drugs (for example, cyclosporine A) can significantly change the cardiovascular safety profile [1, 2, 9] . It should be noted that meta-analyses assessed the safety of different doses of etoricoxib, although it is known that the safety of NSAIDs directly depends on the dose [6–8].

Despite these limitations, data from meta-analyses are valuable for understanding the value of etoricoxib in the treatment of rheumatic diseases. Overall, these data suggest that etoricoxib does not increase the risk of selected atherothrombotic events. It is possible that etoricoxib has a negative effect on cardiovascular mortality, increasing it mainly in individuals with tumors or diseases of the central nervous system [6–9].

In the next step, we analyzed data from large registries including patients who received etoricoxib for rheumatic diseases (see Table 1) [14]. According to a national registry in Taiwan, patients taking etoricoxib 60 mg for rheumatoid arthritis had a reduced risk of cardiovascular events compared with those not using NSAIDs [14]. The advantages of the register are its mononosology, a sufficient observation period, and accurate recording of the doses of etoricoxib and other antirheumatic drugs taken. The register takes into account the Charlson comorbidity index, the incidence of individual comorbid conditions and their treatment [15]. Patients were compared according to basic antirheumatic therapy for the underlying disease. The Taiwanese registry of patients with ankylosing spondylitis, which included more than 10 thousand patients, as well as the registry of patients with rheumatoid arthritis, showed the possibility of a 10-fold reduction in cardiovascular risks when using coxibs for 24 months. in high dosages. But based on the data from this registry, it is impossible to determine the effectiveness and safety of individual coxibs, and therefore the effect of etoricoxib cannot be assessed [16].

When analyzing controlled comparative studies, the most significant is the controlled study by E. Balazcs et al. (2016), which included 1052 patients with ankylosing spondylitis, randomized into 3 groups (etoricoxib 90 mg/day, etoricoxib 60 mg/day, naproxen 1000 mg/day) [17]. The study showed comparable safety of therapy with etoricoxib at both indicated doses and naproxen with regard to thrombotic events, cardiac death, arterial hypertension, and chronic heart failure. The authors of the work noted a trend towards an increase in the frequency of adverse events in the group of patients receiving etoricoxib at a dose of 90 mg/day, compared with this indicator in other groups (the difference was not statistically significant). The results of this work are consistent with the results of the study by van der Heijde et al. (2005), which showed equal safety for 120 and 90 mg/day etoricoxib compared with 1000 mg/day naproxen for 387 patients with ankylosing spondylitis, with a trend towards an increase in the number of cardiovascular events when treated with etoricoxib at a dose of 120 mg/day [18].

The conclusion about the sufficient cardiovascular safety of etoricoxib follows from a comparative analysis of a number of studies, including population-based ones, using this drug [19–28].

Etoricoxib, 7 pcs., 120 mg, film-coated tablets

Pharmacodynamic interaction

Oral anticoagulants (warfarin): In patients receiving warfarin, etoricoxib 120 mg daily was associated with an approximately 13% increase in International Normalized Ratio (INR) prothrombin time. In patients receiving warfarin or similar medicinal products, INR values ​​should be monitored when starting or changing treatment with etoricoxib, especially in the first few days.

Diuretics, angiotensin converting enzyme (ACE) inhibitors: There are reports that non-selective NSAIDs and selective COX-2 inhibitors may reduce the hypotensive effect of ACE inhibitors. This interaction should be taken into account when treating patients taking etoricoxib concomitantly with ACE inhibitors. In patients with impaired renal function (for example, with dehydration or in old age), such a combination may aggravate renal failure.

Acetylsalicylic acid: Etoricoxib can be used concomitantly with acetylsalicylic acid in low doses intended for the prevention of cardiovascular diseases. However, simultaneous administration of low doses of acetylsalicylic acid and etoricoxib may lead to an increased incidence of gastrointestinal ulcers and other complications compared to taking etoricoxib alone. At steady state, etoricoxib 120 mg once daily has no effect on the antiplatelet activity of low-dose acetylsalicylic acid (81 mg daily). The drug does not replace the preventive effect of acetylsalicylic acid in cardiovascular diseases.

Cyclosporine and tacrolimus increase the risk of nephrotoxicity when taking the drug.

Pharmacokinetic interaction

Lithium There is evidence that non-selective NSAIDs and selective COX-2 inhibitors may increase plasma lithium concentrations. This interaction should be taken into account when treating patients taking etoricoxib concomitantly with lithium.

Methotrexate: Two studies examined the effects of the drug at a dose of 60 mg. 90 mg and 120 mg once a day for seven days in patients receiving methotrexate once a week at a dose of 7.5 to 20 mg for rheumatoid arthritis. Etoricoxib at doses of 60 mg and 90 mg had no effect on plasma concentrations (according to AUC) and renal clearance of methotrexate. In one study, etoricoxib 120 mg had no effect on plasma concentrations (AUC) or renal clearance of methotrexate. In another study, etoricoxib 120 mg increased plasma methotrexate concentrations by 28% (AUC) and decreased methotrexate renal clearance by 13%. When co-administering etoricoxib at doses above 90 mg per day and methotrexate, monitor for the possible occurrence of toxic effects of methotrexate.

Oral contraceptives: Taking etoricoxib 120 mg with oral contraceptives containing 35 mcg ethinyl estradiol (EE) and 0.5 to 1 mg norethindrone for 21 days, either simultaneously or 12 hours apart, increases the steady-state AUC0-24h for EE by 50 -60%. However, norethisterone concentrations usually do not increase to a clinically significant extent. This increase in EE concentrations should be taken into account when selecting the appropriate oral contraceptive for concomitant use with etoricoxib. This fact may lead to an increase in the frequency of thromboembolism due to increased exposure to EE.

No significant pharmacokinetic interaction with glucocorticosteroids was detected.

Digoxin: etoricoxib does not affect the steady-state AUC0-24h or the elimination of digoxin. At the same time, etoricoxib increases Cmax (by an average of 33%). which may be important in the development of digoxin overdose.

Rifampicin: Concomitant use of etoricoxib and rifampicin, a potent inducer of hepatic metabolism, resulted in a 65% reduction in the plasma AUC of etoricoxib. This interaction should be considered when etoricoxib is coadministered with rifampicin.

Antacids and ketoconazole (a strong CYP3A4 inhibitor) do not have a clinically significant effect on the pharmacokinetics of etoricoxib.

Discussion of literature data

An analysis of the literature shows that, despite the availability of a large amount of information regarding the cardiovascular safety of etoricoxib in patients with rheumatic diseases, the issue should be considered open. When prescribing etoricoxib to patients with rheumatic diseases, there are pathogenetic prerequisites for both reducing cardiovascular risk by reducing the severity of chronic inflammation, increasing the stability of the atherosclerotic plaque, reducing endothelial dysfunction, neovascularization and extracellular matrix synthesis, and increasing the risk due to the prothrombogenic effects of COX blockade -2, activation of the renin-angiotensin-aldosterone system, fluid retention, tubulo-interstitial changes with the formation of chronic kidney disease and chronic heart failure.

Individual comparative studies involving patients with rheumatoid arthritis or ankylosing spondylitis demonstrate high cardiovascular safety of etoricoxib at dosages of 60–120 mg/day [17, 18, 20, 26, 28]. Several studies have shown a trend towards an increase in the number of cardiovascular events with increasing doses of etoricoxib (without statistical significance) [17, 18]. The results of comparative studies showing the safety of etoricoxib are consistent with data from large Norwegian and Taiwanese registries, which in large samples of patients showed a significant reduction in the risk of cardiovascular events in patients receiving NSAIDs (including coxibs, and in particular etoricoxib) for rheumatoid arthritis or ankylosing arthritis. spondylitis, compared with patients not receiving NSAIDs or receiving non-selective NSAIDs [14, 15, 29]. The MEDAL program showed that in rheumatoid arthritis and osteoarthritis, etoricoxib is not inferior in safety to diclofenac sodium with regard to the development of thrombotic events (myocardial infarction, stroke) [7]. It should be noted that in the studies discussed, patients received etoricoxib for a long time (from 52 weeks to 10 years) [6–9, 14, 15].

The data presented above are contradicted by the results of a number of studies and meta-analyses that included patients with diseases not related to rheumatology and which obviously determine an increased risk of cardiac death and other significant cardiovascular events (patients with tumors, intestinal polyposis, Alzheimer's disease, etc.) [4, 5, 8]. However, the statistical analysis in these studies did not take into account the possible influence of concomitant pathology and its treatment (chemotherapy, glucocorticoids, basic drugs) on the results obtained [1]. These omissions raise doubts about the correctness of the data presented.

In general, it should be noted that when selecting works, we did not find a single study examining the cardiovascular safety of all NSAIDs registered as of January 2021 in the Russian Federation. There are no studies that, within the framework of one study, would show the entire range of problems associated with the pathology of the cardiovascular system in rheumatic patients (atherothrombosis of various locations, chronic heart failure, arterial hypertension, progression of atherosclerosis, rhythm and conduction disorders, progression of chronic disease kidney).

In addition, it is recommended to take into account the errors determined by the design of meta-analyses performed using the network meta-analysis protocol, which compare not only the results of studies, but also the results of meta-analyses.