Warfarin Compliance after Mechanical AVR in the Pediatric Population: Case Series from a Developing Country

Background and Aim: Mechanical prosthetic heart valves exert a lifelong thromboembolic complication requiring continuous antithrombotic therapy. Vitamin K antagonist is the recommended therapy of choice along with meticulous INR monitoring to achieve and maintain an INR of 2.0 - 3.0. The study aimed to assess the compliance of anticoagulant therapy in pediatric patients after AVR and to highlight the challenges faced during follow-ups. Methods: A retrospective study was conducted at NICVD Hospital in Kara-chi, Pakistan for a time frame of 2 years from 2020-2021 where 7 patients were selected. Data were collected using hospital medical records and then validated through a phone call mediated structured questionnaire-based in-terview. Results: 2 out of 7 patients in the case series were compliant to regular follow-ups and had their INR in the desired range owing to their higher education status and access to INR clinic for regular follow-up in urban set-ting. Younger patients in the case series were non-compliant. 4 out of 7 patients who were on dual anti-coagulant regimens including warfarin and aspirin were either closer or within the range than compared to those on single drug regimen. Conclusion: Compliance was observed in patients who had fa-vorable demographics and higher education. Multiple recent trials including PROACT and PROACT XA are underway to develop novel treatment options apart from warfarin after mechanical aortic valve replacement. Home-based INR testing kits provide easy access to regular testing in remote areas. Mul-ti-center studies are required for in-depth analysis regarding reasons of non-compliance in pediatric population.


Introduction
Rheumatic heart disease (RHD) is a global burden that's affecting almost 33 million people mostly in low socioeconomic countries. RHD manifests in the form of carditis and valvular disorders of which mitral and aortic valves are most commonly affected. Definitive management includes transcatheter or surgical replacement of the valve [1].
Prosthetic heart valves have a lifelong risk of thromboembolic complications requiring continuous antithrombotic therapy that needs meticulous monitoring of INR throughout the lifetime. After valve replacement with a mechanical device American College of Cardiology has recommended the use of anticoagulation therapy with a vitamin K antagonist (VKA) to achieve and maintain an INR of 2.0 -3.0 in the adult population [2] [3]. According to a meta-analysis conducted in 2019, the paediatric and adolescent populations were also maintained within INR of 2.0 -3.0 and none developed a late hemorrhagic event [4]. Poor control of INR after mechanical and bioprosthetic AVR, subjects these patients to frequent thromboembolic complications mainly consisting of transient ischemic event, stroke and pulmonary embolism due to systemic emboli with an incidence of 1.8 and 8 events per 100 patient-years on and off anticoagulation, respectively [5].
Achieving safe and effective anticoagulation in children and adolescent is difficult owing to the difference in developmental hemostasis physiology and drug metabolism mechanism in children making patients more prone to thromboembolic complications. Dietary factors in which the most significant effect is seen with consumption of green vegetables, multivitamins or diet rich in vitamin K that suppresses the anticoagulant effect of warfarin were observed [6].

Case Series
A retrospective study was conducted at NICVD Hospital in Karachi, Pakistan for a time frame of 2 years from 2020-2021. RHD patients within the age group of 5 -18 years who underwent aortic valve replacement (AVR) with Medtronic open pivot mechanical heart valve were included. Those outside this age group with non-rheumatic heart disease (congenital heart disease), with involvement of any other valve and replacement with bioprosthetic valves were excluded. The data was collected using hospital medical records and then validated by the patients or their guardian in the study after informed consent through a phone call mediated structured questionnaire-based interview. (See Table 1 It can also rightly be pointed out that achieving safe and effective levels of anticoagulation in children is more challenging than in adults, due to the difference in physiology and drug metabolism [7]. Another prospective randomized trail PROACT Xa started in May 2020 with estimated study completion by July 2024, comparing apixaban with warfarin in patients with On-X AVR [9]. In ARISTOTLE trial (Apixaban for reduction in stroke and other thromboembolic events in atrial fibrillation), apixaban arm was World Journal of Cardiovascular Surgery more effective in preventing ischemic or hemorrhagic stroke versus warfarin in patient with atrial fibrillation [10]. Similarly, a meta-analysis by Touma et al., reported that compared to warfarin, apixaban showed lower risk of bleeding in patients requiring prolonged anticoagulation [11]. The results of PROACT Xa study can generate novel treatment options, apart from warfarin, for On-X AVR.
To improve compliance home-based INR testing kits should be introduced to provide hassle free regular testing in remote areas. In a study conducted in Minnesota, in-home monitoring group of patients who used a Coaguchek Xs System were compared to the in-clinic group of patients, and the results were similar in terms of time taken to achieve therapeutic range [10]. No significant difference was observed in cases of major bleeding or TE between the two groups, however, monitoring in-home is more convenient and suited to the patient as it saves resources [10]. The initial cost of the Coaguchek Xs System is high ranging in between Rs 32,000 -40,000, however eventually it is more beneficial since one lab test costs approximately Rs 800 whereas Coaguchek Xs testing strip costs Rs 500 [12].
Our study had numerous limitations, primarily it had only 7 patients from a single hospital set up, who underwent AVR. Multi-center studies will help achieve more holistic understanding. Demographical location was another limitation where majority of our patients belonged to rural areas. Hence cohort studies will give a just comparison of the two socio-economic groups. It is also noticed that due to limited facility of INR monitoring clinics in rural areas, there's a need to invest and train the paramedical staff to cater to the patients. Lastly, INR should be strictly checked on a regular basis for patients on warfarin therapy identical to the DOTS protocol for tuberculosis.

Conclusion
The study evaluated the level of compliance of oral anticoagulation therapy in pediatric and adolescent population after mechanical AVR in patients with RHD. It highlights the reasons for non-compliance and provides suggestions to overcome them. It was noticed that the major cause for non-compliance was poor follow-ups to INR monitoring which can be improved with home-based INR testing kits and using recent advances in anticoagulation therapy which are not INR dependent. There is still a need for in-depth discussion to obtain more information about the reasons for non-compliance from multi-center studies.