EFFICIENCY OF PREVENTION OF VENOUS THROMBOEMBOLIC COMPLICATIONS IN ENDOPROSTHETICS OF LARGE JOINTS IN PATIENTS WITH RHEUMATOID ARTHRITIS AND OSTEOARTHROSIS (A PROSPECTIVE STUDY)
Nasonova Scientific Research Institute of Rheumatology,
Moscow, Russia
Currently, 30-58 % of patients with rheumatoid diseases (RD) receive orthopedic surgery. The common operations are knee joint endoprosthetics (57 %) and hip joint endoprosthetics (38 %) [1, 2]. According to the results of the world-wide studies, it is recommended to conduct prevention of venous thromboembolic complications (VTEC) for patients after knee and hip joint replacement [3, 4]. Deep venous thrombosis is identified in 34-57 % of patients who receive orthopedic interventions and do not receive specific prevention of VTEC [5]. The relationship between the chronical inflammatory disease (such as RA) and development of thromboembolic complications has been proved documentarily: hypercoagulation is induced by active systemic inflammation and production of cytokines (TNF-alpha and IL-1) leading to endothelial dysfunction, decreasing regulation of C protein, i.e. natural anticoagulant, and subsequent inhibition of fibrinolysis [6, 7]. Previous surgical interventions, specific drug therapy, hypodynamia and other concurrent diseases present the additional factors of risk of VTEC in patients with RA [8]. However there are some contradictive findings about the rates of VTEC in patients with RA and OA. Some studies show the similar rates of VTEC after joint replacement [9, 10]. A large-scale retrospective study by Y.Niki et al. [11] shows the lower risk of VTEC in patients with RA.
Despite of the important features of pathogenesis in patients with RD, according to the materials from the Conference of antithromboembolic therapy 2012, the common techniques of prevention from American College of Chest Physicians (ACCP) are used [5]. The basic drug measures include some various anticoagulants (AC) reducing the risk of development of thromboembolic complications: unfractionated heparin (heparin sodium, heparin calcium), low molecular weight heparin (enoxaparin sodium, nadroparin calcium, dalteparin sodium), vitamin K antagonists (warfarin), fondaparinux sodium. However all of them have some disadvantages: difficult prediction of pharmacokinetics, need for continuous monitoring of coagulogram, risk of side effects (thrombocytopenia), frequent parenteral introduction uncomfortable for long term AC prevention and use in outhospital conditions [4]. Also it is necessary to note appearance of oral AC such as dabigatran ethoxylate and rivaroxaban which have some advantages in comparison with other drugs: standard dosage, single oral intake, rapid appearance of effect, predicted pharmacokinetics, absence of necessary laboratory control, a possibility for long term use for prevention of thromboembolic complications [12, 13].
Despite of multiple studies describing efficiency of different AC and proper descriptions of preventive techniques for traumatologist-orthopedist who plans endoprosthetics for a patient with RA, for choice of AC therapy (along with estimation of risk of bleeding and analysis of other factors relating to VTEC) it is necessary to estimate the influence of constantly used pharmaceuticals on hemostasis.
Most patients with RA and SLE receive therapy with different groups of medication including non-steroidal anti-inflammatory drugs (NSAID), glucocorticoids (GC), disease-modifying anti-rheumatic drug (DMARD) and genetically engineered biological drugs. DMARD play significant role in symptomatic management of such patients. COX-1 inhibitors hinder formation of thromboxane A2 resulting in further disorder of thromboxane-dependent aggregation of platelets and increasing risk of bleeding. It means that COX-1 inhibitors should not be described within a week before surgery [14, 15]. But it is known that COX-2 inhibitors do not influence on the mechanism of platelet inhibition, i.e. they can be used before surgery [16].
GCs are used for treatment of acute RA and SLE, i.e. their presurgical use should be justified. GCs intensify formation of red blood cells and platelets, as well as action of NSAID. Long term use of GCs leads to secondary adrenal insufficiency because of constant suppression of release of corticotropin-releasing hormone from the hypothalamus. Such patients need for stress dosage of hydrocortisone (50-100 mg) and 100-150 mg of intravenous methylprednisolone with following decreasing dosage after surgery. Moreover, long term administration of GCs is associated with bad quality of bone tissue that requires long term anti-resorption therapy [17].
NSAID relates to the highest influence on delay or prevention of destruction of joints in RA. They include methotrexate, leflunomide, sulfasalazine, azathioprine, hydroxychloroquine and some genetically engineered biological drugs [17].
The main task of such drugs is control of activity of the disease. Ingegnoli F. et al. investigated the inflammatory and fibrinolysis markers at the background of therapy with infliximab and showed that such therapy decreases inflammation and inhibition of fibrinolysis that favors decreasing risk of VTEC [18]. However Ruyssen-Wittrand A. noted the increasing risk of thrombosis and negative influence on the rate of recovery of the postsurgical wound [19]. The issue about presurgical and postsurgical administration is still actual.
There are some studies indicating the safety of treatment with disease modifying drugs and genetically engineered biological drugs after surgery [15, 20]. D.M. Grennan et al. [15] performed one-year observation of 388 patients with RA after arthroplasty of the big joints and noted the better outcomes in the patients with continuous postsurgical intake of methotrexate in comparison with the patients with temporary cancel of the drugs.
Shreekumar R. et al. [20] analyzed the same population of the patients 10 years after arthroplasty. They found that long term use of methotrexate was not associated with any additional cases of deep bone infections. The special interest relates to patients with involved kidneys in RA and SLE. Most authors recommend to cancel methotrexate a week before surgery and to continue administration after 1-2 weeks [7]. It is associated with the fact that the postsurgical period can cause additional stress with worsening function of the kidneys and lead to renal insufficiency with increasing toxicity of methotrexate. Observation of the patients with RA after arthroplasty resulted in making the conclusions about safety and efficiency of TNF inhibitors in short period of cancellation before and after surgery [21].
Objective – to analyze the rate of development of venous thromboembolic complications in patients with rheumatoid arthritis after endoprosthetics of the large joints, to compare the schemes of drug therapy for such complications and to estimate their efficiency.
MATERIALS AND METHODS
We analyzed the results of treatment of 384 patients with confirmed diagnosis of RA and OA. The patients received surgical treatment in the department of traumatology and orthopedics in Nasonova Scientific Research Institute of Rheumatology within the period from March 1, 2013 to May 28, 2015. Prevention of VTEC was conducted for all patients in concordance with the Russian clinical recommendations for diagnostics, treatment and prevention of venous thromboembolic complications [22] and the Clinical recommendations from the Association of Rheumatologists of Russia 2010 [23].
The inclusion criteria were men and women at the age > 20 with reliable diagnosis of RA and OA who were admitted for replacement of the big joints of the lower extremities, residence in Moscow and its districts, available written consent.
The exclusion criteria were presence of concurrent pathology with difficulties of interpretation of results, for example, severe injuries to the brain, stroke, decompensated liver cirrhosis with events of hepatic encephalopathy, severe renal insufficiency (the rate of hepatic encephalopathy < 30 ml/min), uncontrolled arterial hypertension, myocardial infarction within the following 3 months, gastrointestinal or urogenital bleeding, liver dysfunction (increasing levels of ALT and ACT more than 3 times in comparison with the upper reference). Also we excluded the patients with previous surgery for the lower extremities within 3 months before admission, with high risk or impossible independent walking, the patients at the age > 70 and with contraindications for AC.
All registered patients received the clinical examination with estimation of the state of the superficial veins, ultrasonic duplex scanning of the veins of the lower extremities before surgery, on days 4-7, 14 and 28 after surgery; the laboratory analysis (total blood analysis, biochemical blood analysis, coagulogram, D-dimer) before surgery and on days 1, 7, 14 and 28 after surgery. The questionnaire survey with the model by Caprini [24] was used for individual estimation of the risk factors of venous thrombembolia. The HAS-BLED score for Major bleeding risk was used [25]. Intra- and postsurgical blood loss was estimated within 5 days after surgery. Major bleedings were fatal bleedings, bleedings with decreasing hemoglobin by 20 g/l and more with need for transfusion of 2 or more units of packed red cells, bleedings requiring cancellation of AC. Other potential risk factors were sex, weight, the main disease (RA or OA), the type of anesthesia, time of tourniquet (for knee joint replacement), early/late activation, wearing of compression clothes. Medical prevention of VTEC was realized with nadroparin calcium, dabigatran etexilate and combined therapy with these drugs.
The statistical analysis was conducted with Statistica 6.1 (Statsoft Inc., USA) and IBM SPSS Statistics 22 (IBM Inc., USA). The quantitative signs were presented as the mean and mean-square deviation (M ± s; in case of normal distribution) or as median and quartiles (Me [Q1; Q3]; relative frequencies and 95 % CI for binary features and in the case when presentation of descriptive statistics in other form does not allow making conclusions about higher or lower values in one or another group). The qualitative signs were presented as absolute and relative values. The level of p < 0.05 was considered as statistically significant.
RESULTS AND DISCUSSION
The study included 384 patients. 14 (3.6 %) cases were excluded from the analysis because of the following reasons: prescription of AC before surgery without compliance with the clinical guidelines (5), discontinuation of AC after surgery within the period from 1 to 30 days (7), incorrect dosages of AC (2).
The final group included 370 patients: 131 patients with RA (35.4 %) and 239 patients with OA (64.6 %). Knee joint replacement (151 operations) was conducted for 72 patients with RA and 79 patients with OA. Hip joint replacement 9219 operations) was conducted for 59 patients with RA and 160 patients with OA. The mean age of the patients with RA was 52.2, with OA – 64.5. There were 263 women (71 %) and 107 men (29 %).
For the comparative analysis of efficiency of AC therapy each group of the patients was distributed into the subgroups according to the type of drug preventive care. The first subgroup received prevention of VTEC with use of LMH (nadroparin calcium as single therapy). The drug was prescribed at 12 hours after surgery (0.1 ml per 10 kg of body weight per day). The therapy lasted for 30-35 days. The second subgroup received preventive care with use of NOACs (dabigatran etexilate as single therapy). The drug was prescribed on 2nd or 3rd day after surgery, but not earlier than at 1-2 hours after removal of the epidural catheter, with the common preventive dosage of 220 mg per day. Therapy lasted for 30-35 days. The third subgroup received combined prevention of VTEC. The first stage (12 hours after surgery) included LMH (nadroparin calcium) followed by shift to NOACs (dabigatran etexilate) after removal of the epidural catheter during 28-30 days. The fourth subgroup included the patients with RA who received NSAID and disease modifying drugs with minimal amount of risk factors of VTEC. That group received preventive care of VTEC by means of non-pharmaceutical techniques (elastic compression for the lower extremities and early activation on the 1st day after surgery). Such patients were under special control: USDG for the veins of the lower extremities on days 3, 7, 14 and 28 after surgery, coagulogram + D-dimer (each 3 days).
368 patients (98.5 %) received drug-free prevention of VTEC (elastic dressing for the legs or the certified postsurgical compression clothes with graduated compression). The risk of VTEC was estimated for each patient according to the risk factors (the table 1). The analysis of the data showed that such factors as age, percentage ratio of men, body mass index and concurrent diseases were significantly higher in the patients with OA. However the laboratory results showed the higher amount of hypercoagulation events in the patients with RA before surgery (the table 1).
| Table 1 | ||||||||||||
| The basic features and drug therapy for VTEC in patients with OA or RA before surgery. The values n (%), if other values are not indicated | ||||||||||||
Most patients received preventive care with use of single AC – 84.3 % of the cases (312 patients). The remaining 62 (16.7 %) patients received combined AC therapy. 13 (3.5 %) patients with RA did not receive drug therapy.
Postsurgical thromboembolic complications were registered in 16 (4.3 %) patients including 2 (0.5 %) patients with RA and 14 (3.8 %) patients with OA (the table 2). Distal deep venous thrombosis developed in both patients with RA. The first patient with RA received prevention of VTEC with dabigatran etexilate. Venous thrombosis in the lower extremities developed on 15th day after hip joint replacement. According to our opinion, the cause of thrombosis was late prescription of the drug (on 3rd day after surgery). It was the reason for initiation of combined AC therapy in all subsequent patients. DVT was diagnosed in the second patient with RA from the 4th subgroup at 3 months after surgery. The additional examination identified genetic thrombophilia, but it was not associated with endoprosthetics. Among the patients with OA, distal deep venous thrombosis developed in 13 patients: 10 patients from the group of single therapy with nadroparin calcium at the background of unfounded early cancellation of AC after hospital discharge within the terms from 15 to 28 days, and in 4 patients with single therapy with dabigatran etexilate on the days 7-15 because of late prescription of the drug (3rd day after surgery). Pulmonary embolism was not registered in none of the cases.
| Table 2 | |||||||||||||
| The rate of development of VTEC in patients with RA and OA in early postsurgical period. The values n (%), if other values are not indicated | |||||||||||||
16 cases of VTEC included 10 (62.5 %) asymptomatic cases and 6 (37.5 %) cases with development of the clinicolaboratory symptom complex. Both cases of thrombosis were asymptomatic in the group of RA. As for the cases of distal thrombosis in the group of OA, 5 cases included the clinicolaboratory symptom complex and 8 cases were asymptomatic; proximal thrombosis with development of the symptom complex.
Fatal bleedings were not identified in none of the cases. It supports the safety of AC therapy. Major bleedings were found in 6 (1.6 %) patients with OA and in 2 (0.5 %) patients with RA. The main causes were postsurgical draining and the wound.
In the present study we could not completely estimate the risks of the associated factors of VTEC, because the patients with RA (in contrast to OA) receive different combinations of the drugs for treatment of the main disease through their lives (NSAIDs, disease-modifying agents, genetically engineered biological drugs). The effect of these drugs and the risk of VTEC are unclear. Therefore, risk/benefit ratio of AC remains unclear for patients with RA.
CONCLUSION
1. Despite of the significant amount of the risk factors in similar conditions, the rate of VTEC is significantly lower in the patients with RA in comparison with OA.
2. The amount of asymptomatic deep venous thrombosis is higher than the rate of thrombosis with development of the clinicolaboratory complex of the symptoms in both comparison groups.
3. Combined AC prevention of VTEC for RA and OA is the most efficient and safe. No cases of VTEC were registered. Some cases of VTEC were identified in the patients with RA and OA who received single therapy with nadroparin calcium or dabigatran etexilate.