Comparative Study of Compliance and Factors Affecting Compliance among Commonly Used Drugs in Deep Vein Thrombosis Patients

Objectives: The objective of current research was to identify the compliance of antithrombotic drug (heparin, warfarin and Rivaroxaban) and factors of non-compliance associated with heparin, warfarin and rivaroxaban. Methodology: A cross-sectional, observational study was conducted on patients suffering from Original Research Article Ali et al.; JPRI, 33(47A): 221-229, 2021; Article no.JPRI.74308 222 Deep Vein Thrombosis (DVT) at government teaching hospital of Larkana. 348 DVT patients were selected by using online sample calculator software. Data was collected by using pre validated questionnaire after taking patient consent; finally the data was analyzed with statistical package of social sciences (SPSS) version 25. Results: The compliance with rivaroxaban was present in 103 (80.5%) patients followed by heparin drug compliance in 95 (74.2%) DVT patients and warfarin drug compliance in 98 (76.6%) DVT patients. Non-compliance factors with rivaroxaban were; cost in 4 (16.0%) patients, polypharmacy in 6 (24.0%) patients, side effects in 4 (16.0%) patients and prolong therapy in 11 (44.0%) patients. Non-compliance factors with heparin were; monitoring in 13 (39.4%) patients, diet restriction in 6 (18.2%) patients, injectable in 10 (30.3%) patients and ADR in 4 (12.1%) patients. Non-compliance factors with warfarin were; cost in 4 (13.3%) patients, polypharmacy in 8 (26.7%) patients, prolong therapy in 5 (16.7%) patients and ADR in 13 (43.3%) patients. Conclusion: This study concludes that rate of drug compliance was high in patients of DVT with rivaroxaban followed by warfarin and heparin, whereas long duration of therapy, polypharmacy, side effects of therapy, cost of therapy, continuous monitoring, injectables, diet restrictions and ADRs of therapy were the most commonly reported factors of non-compliance.


INTRODUCTION
Deep vein thrombosis (DVT) is simply defined as "Presence of a blood clot (commonly known as thrombus) in deep vein of legs or rarely in arms" [1]. Deep vein thrombosis is the cardiovascular disease in which one or more than one blood clot is formed in large veins of human body. Presence of single blood clot in vein is called formation of thrombus, whereas presence of multiple blood clot in vein is called formation of thrombi. Thrombus or thrombi are responsible for partial or complete blockage of blood circulation in veins. In majority of cases deep vein thrombosis is formed in legs but it can also be observed either in veins of arms or in mesenteric veins or in cerebral veins [1,2].
Anticoagulation is an important part of DVT therapy. Majority of the DVT patients are treated with oral anticoagulant drugs, whereas few patient requires combination therapy. Proximal deep veins are mostly affected in severe thrombus. In acute phase of disease these patients are treated with mechanical-and catheter-directed thrombolysis (CDT), which causes the rapid lysis of thrombus and decreases the risk of increased incidence of post-thrombotic syndrome [3,4]. Such procedures are often used to manage acute ischemia of the limbs due to arterial thrombosis, but there is an elevated risk of ischemiareperfusion damage [5,6]. However, thrombolytic treatment is directly correlated with higher risk of bleeding that also increased the risk of mortality in patients of DVT [7-10].
The main objectives in management of DVT are; Inhibits pulmonary embolism (PE). Decrease the increasing rate of morbidity. Decrease the increasing risk of postphlebitic syndrome development. Heparin is most commonly used drug for treatment of DVT. It is a heterogeneous polysaccharide mixture containing different fragments of polysaccharide having different molecular weights but similar therapeutic activity. In normal mechanism, activated factor X act on prothrombin protein and convert it into its active form i.e., thrombin. Protein thrombin act on fibrinogen protein and convert it into its active form i.e., fibrin. It is long string protein that creates mesh like covering around wound or in blood vessels. These fibrin covering accumulates the platelets on its surface and form blood clot that stop or decreased the blood flow. Basically, heparin have two fragments i.e., high and low molecular weight. Although both fragments have similar therapeutic effects but different mode of action in treatment of DVT. High Molecular Weight Heparin (HMWH): These fragments produced their anticoagulant action by directly affecting the antithrombin III (ATIII) and inhibit the process of thrombin. Antithrombin III, primary anticoagulant of human body, inactivates the thrombin as well as suppresses the activated factor X activity in process of coagulation. Low Molecular Weight Heparin (LMWH): These fragments produced their anticoagulant action by directly affecting on activated factor X and inhibit their activity [11][12][13]. Unfractionated Heparin (UFH) is mostly used in hospitals not only for treatment of DVT but also for prevention of DVT. It is administered to patient either intravenously (IV) or subcutaneously (SC) for prevention. In case of prevention, heparin is administered few hours before surgery whereas in case of treatment, heparin is administered few day after surgery. It is administered to patient IV for treatment. In case of treatment, initially patient treated with UFH in hospital and then after discharge treated either by LMWH or warfarin [11][12][13][14].
Warfarin is oral anticoagulant, most commonly used for long-term treatment to avoid the reoccurrence of clot during the management of DVT. It is blood thinner commonly advice during DVT management in home. Warfarin shows the anticoagulant action in human body by antagonizing the vitamin K as well as responsible for reduction of different factors that play direct or indirect key role in blood clotting. Warfarin directly act on vitamin K reductase enzyme i.e., vitamin K epoxide reductase complex 1 (VKORC1) and inhibit its activity resulting in formation of vitamin K in reduced form. VKORC1 is very important enzyme that play key role in activation of vitamin K in body and its reduction decreased the vitamin K in function form resulting in decreased synthesis of clotting factors. Depletion of functional vitamin K also decreased the glutamate residues carboxylation that not only results in decreased formation of different coagulation factors such as II, VII, IX, and X but also decreased the formation of anticoagulant proteins such as C and S. That finally, decreased the prothrombin levels and indirectly decreased the thrombin production and decreased the clotting of blood as shown in Fig.  1. It is administered orally once in a day. It is advised that it should be administered either in afternoon or in evening. Its effect vary from patient to patients and high depends upon patients like response of patient towards metabolism of drug or quantity of vitamin K taken by patient daily, genetics, presence of different vitamin K clotting factors and binding proteins, comorbidities, any sort of drug interaction or side effect [15][16][17].
Rivaroxaban is also an oral anticoagulant, most commonly used for management of DVT. It is not only used for treatment of DVT and PE but also used for preventing recurrent DVT and PE. Its mechanism of action is somehow to similar heparin. Rivaroxaban directly inhibit the activated factor X responsible for conversion of prothrombin into thrombin form, which act on fibrinogen and convert it into fibrin that form mesh around wound or in blood vessels and accumulates the platelets on its surface and form blood clot that stop or decreased the blood flow.
Rivaroxaban directly inhibit the activated factor X and prevent the all mechanism resulting in decreasing the clot formation process [18][19][20]. It is administered orally in divided doses in a day. It is advised that it should be administered either in divided doses to maintain its concentration in blood for achieving therapeutic efficacy [18][19][20].

Design of Study
Design of current hospital based study was descriptive cross-sectional.

Sample Size
Sample size was calculated by using OpenEpi software. After entering the required information in software the answer was 348.

Sampling Method
Patients were selected from medicine department of hospital by using the nonprobability purposive sampling technique.

Duration of Study
Data of 384 patients was collected within six months.

Inclusion Criteria
Only those patient were included in the research whose age was from 18-65 years and were diagnosed with DVT. Only those patients were included in the study who were treated either with Rivaroxaban or Heparin or Warfarin.

Data Collection Method
Patients of deep vein thrombosis who fulfilled the inclusion criteria of research were enrolled in research. A specially designed pre validated questionnaire was used for interviewing enrolled patients and for collection of data.

Statistical Analysis
Collected data was interpreted with latest version 25.0 of SPSS.

Compliance of Rivaroxaban
Drug compliance with rivaroxaban drug was present in 103 (80.5%) patients and noncompliance was present in 25 (19.5%) patients.

Compliance of Heparin
Drug compliance with heparin drug was present in 95 (74.2%) patients and non-compliance was present in 33 (25.8%) patients.

Compliance of Warfarin
Drug compliance with warfarin drug was present in 98 (76.6%) patients and non-compliance was present in 30 (23.4%) patients.

DISCUSSION
Therefore, current cross-sectional research was designed in setting of tertiary care hospital of Larkana, where diagnosed patients of DVT were enrolled from medicine department and evaluated for commonly reported clinical sign and symptoms of DVT, patients drug compliance with Heparin, Warfarin and Rivaroxaban drugs and associated non-compliance factors with these antithrombotic drugs.
In current research overall drug compliance with antithrombotic drugs was reported in 296 (77.1%) DVT patients, whereas drug compliance with rivaroxaban was present in 103 (80.5%) patients followed by heparin drug compliance in 95 (74.2%) DVT patients and warfarin drug compliance in 98 (76.6%) patients. A similar study by Kang, JM, et al., [21] reported the overall drug compliance 93.8% with antithrombotic  [24] and reported the higher drug compliance with rivaroxaban followed by heparin and warfarin [25][26][27].

CONCLUSION
This study concludes that the rate of drug compliance was high with rivaroxaban followed by warfarin and heparin. Most commonly reported factor of non-compliance with rivaroxaban was long duration of therapy followed by polypharmacy, side effects of therapy and cost of therapy. Most commonly reported factor of non-compliance with heparin was continuous monitoring followed by injectables, diet restrictions and ADRs of therapy. Most commonly reported factor of non-compliance with warfarin was ADRs of therapy followed by polypharmacy, long duration of therapy and cost of therapy.

CONSENT AND ETHICAL APPROVAL
As per international standard or university standard guideline Patient's consent and ethical approval has been collected and preserved by the authors.