Expert Opinion on the Use of Novel Oral Anticoagulants for Stroke Prevention in Non-valvular Atrial Fibrillation for the Primary Care Setting in India: A Literature Review

Atrial fibrillation (AF), the most prevalent cardiac arrhythmia encountered in clinical practice, is linked with substantial morbidity and mortality due to accompanying risk of stroke and thromboembolism. Patients with AF are at a five-fold higher risk of suffering from a stroke. Anticoagulation therapy, with either vitamin K antagonists or novel oral anticoagulants (NOACs), is a standard approach to reduce the risk. Consultant physicians (CPs) in India are the primary point of contact for the majority of patients before they approach a specialist. The CPs may face challenges in screening and diagnosing AF patients. The apprehensions associated with managing AF patients with anticoagulants, further add to the challenges of a CP. This review aimed to identify the key decision points for the CPs to diagnose AF and initiate anticoagulation in patients with non-valvular AF (NVAF) and bring to the table a simplified recommendation supported by expert opinion and guidelines for stroke prevention in NVAF patients.

valvular AF (NVAF) and bring to the table a simplified recommendation supported by expert opinion and guidelines for stroke prevention in NVAF patients.
All the experts who were invited for the preceding advisory board are of ~20 to 30 years of clinical experience in the management of NVAF and are very well aware of the evolving landscape of anticoagulants. Their expert opinion was weighed along with the evidence from the literature including the recommendations from the guidelines to propose the protocol for the management of stroke prevention in AF suitable for the primary care setting in India.

Recent guidelines
Various clinical practice guidelines have provided recommendations for the prevention of stroke in patients with AF. The recommendations made by the 2019 American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines and the Heart Rhythm Society (AHA/ACC/HRS Focused Update of the latest AHA/ACC/HRS Guideline) [11], the 2020 European Society of Cardiology (ESC) [12], and the 2021 European Heart Rhythm Association Practical Guide [13] are summarized in Table 1.   [11], the 2020 European Society of Cardiology (ESC) [12], and the 2021 European Heart Rhythm Association Practical Guide [13].

Screening
In 20-45% of stroke cases, the underlying AF is detected at the time of stroke. The reason for underdiagnosis of AF can be because of a significant proportion of cryptogenic strokes attributed to undetected AF. AF remains asymptomatic in almost one-third of the cases and most of the symptomatic patients have atypical symptoms [14]. Paroxysmal AF can progress to sustained forms of AF within the first year and the progression rate ranges from 8.6% to 15% [15]. Unattended sustained AF has a high risk of stroke and heart failure (HF). Hence, for many patients, the steps required to prevent sustained AF should begin early. Stroke is preventable with a 66% reduction in risk when appropriate anticoagulation therapy is given to eligible patients with AF. Hence screening of patients for AF is vital to prevent stroke in patients [14].
The conventional risk factors for AF include coronary heart disease, hypertension, heart failure, left ventricular diastolic dysfunction, diabetes, hyperthyroidism, obesity, and valvular heart disease [16]. The experts in the advisory board opined that CPs should assess the high-risk patients for AF and can follow a checklist to identify patients ( Figure 1). The panelists suggested that if the electrocardiogram (ECG) is normal, the patients should be followed up for their primary condition for which they visited. The CPs can consider doing echocardiography if the patient has cardiac co-morbidities.

Diagnosis
AF is suspected when an irregular pulse is observed in a patient and must be confirmed using a 12-lead ECG [17]. The diagnosis of AF requires documentation of ECG recorded cardiac rhythm showing the typical pattern of AF where one episode lasts for at least 30 seconds. When clinical suspicion of atrial fibrillation persists despite normal ECG, a Holter monitor (24-hour recording) or event monitor (seven to 30-day recording) may be warranted [17]. There are five types of AF identified based on the presentation, duration, and spontaneous termination of AF episodes ( Table 2) [12]. The anticoagulation strategy however does not depend upon the type of AF.

Sr. no.
Type of AF Presentation

Management
The congestive heart failure, hypertension, age ≥75 (doubled), diabetes, stroke (doubled), vascular disease, age 65-74, and sex (female) (CHA 2 DS 2 -VASc) score is used to identify the risk of thromboembolism in AF patients and hypertension, abnormal renal and liver function, stroke, bleeding, labile INR, elderly, drugs or alcohol (HAS-BLED) score assesses the risk of bleeding in anticoagulation ( Age (e.g., > 65) 1 Drugs (e.g., concomitant aspirin or NSAIDs) or alcohol 1 Maximum score 9 HAS-BLED score of ≥3 warrants for regular clinical review and follow-up

Evolution of treatment
The management strategies for stroke prevention have evolved substantially in the past three decades. Novel drugs have been developed and robust clinical studies and meta-analyses have supported the use of anticoagulants for stroke prevention. Some of the landmark events in the evolution of stroke prevention management have been presented in Figure 2 [12,20].

Issues with warfarin
Warfarin, a vitamin K antagonist is the most widely used anticoagulant. However, in the recent past, its use for the same has decreased due to many challenges including unreliable INR values, unpredictable outcomes, and need for continuous monitoring and availability of NOACs [21]. Warfarin loading doses may result in a hypercoagulable state and potential clot formation because of significant reductions in protein C and protein S levels ( Table 4) [22].   [26]. Apixaban was associated with fewer major bleeds in comparison to all other NOACs. Figure 3 depicts the checklist for CPs designed based on the expert opinion of the advisors.

Tailor-Made Therapy
Elderly and very elderly: Elderly patients (age above 75 years) [27] are more prone to thromboembolic events as well as have an increased risk of bleeding [28]. The factors apart from age that are responsible for venous thromboembolism (VTE) include the presence of comorbid conditions, increased risk of falls, renal insufficiency, potential drug interactions, and dementia [27]. The Fit fOR The Aged (FORTA) list is a drug classification combining positive and negative labeling of drugs frequently prescribed to elderly patients [29]. As per the consensus, apixaban has been rated as FORTA "A" (i.e., A-bsolutely = indispensable drug, clear-cut benefit in terms of efficacy/safety ratio proven in elderly patients for a given indication), while warfarin, dabigatran, and rivaroxaban are given FORTA B label (i.e., B-eneficial = drugs with proven or obvious efficacy in the elderly, but limited extent of effect or safety concerns) [30].

Renal impairment
Patients with chronic kidney disease (CKD) are at two to three times higher risk of developing AF as compared to the general population. The risk of thromboembolism due to AF in CKD patients is independently higher as compared to those without CKD [31][32][33].
The NOACs are eliminated renally to varying extent and hence dose adjustment is warranted to manage the risk of bleeding. The calculation of dose reduction is critical as either efficacy or safety is affected with inappropriate doses [34]. Warfarin has been reported to cause renal damage in patients with CKD and is also associated with the progression of renal disease [35]. Apixaban is approved for patients with creatinine clearance <15 mL/min including dialysis for all indications in India [36]. The dosing of NOACs based on stages of CKD has been depicted in Figure 4

Impaired hepatic function
NOACs undergo significant metabolism in the liver. Hepatic impairment thus may lead to an increase in drug levels and decrease in coagulation factors and may result in consequent bleeding. Some NOACs are dependent on cytochrome P450 enzymes for metabolism and in case of hepatic impairment, the activity of these enzymes may be altered. Hence, dose adjustment in patients with hepatic impairment is warranted ( Figure 5) [41].

Patients with increased risk of GI bleeding
Dabigatran and rivaroxaban are associated with more than 50% and more than a two-fold increased risk of gastrointestinal (GI) bleeding, respectively, when compared to warfarin [42]. Apixaban has been shown to have comparable major GI bleeds to warfarin. For patients at high risk of GI bleeding, ESC 2016 recommends the use of VKA or NOAC other than dabigatran 150 mg or rivaroxaban 20 mg (class IIa, level B) [20].

Extreme low body weight
The efficacy of NOACs is directly correlated to their plasma concentrations. Since the distribution volume is linked to body weight, extreme body weight can affect their efficacy or safety. Recommendations for dose adjustment based on body weight are represented in

Minor procedures
The EHRA has put together recommendations for temporarily discontinuing anticoagulants for patients undergoing minor invasive procedures ( Figure 6) [13,44]. Due to the increased risk of bleeding, anticoagulant therapy may require temporary cessation in some patients. The conditions and timings for cessation and re-initiating anticoagulants depend on the type of procedure and patient characteristics. The decision of when to stop the NOACs therapy before the invasive procedure is dependent on renal function, type of surgery, and the risk of bleeding. In case a minor surgical intervention which is associated with minimal bleeding risk and/or adequate local hemostasis can be practiced, NOAC therapy can be restarted after six hours. Recommendations regarding restarting NOACs after invasive procedures with lowrisk or high-risk bleeding are presented in  Caution should be exercised while using NOACs, especially in patients with co-morbidities. The recommendations for the tailor-made for individual patients with NVAF are summarized in Table  7 [27,36,46].

Recommendation
Please consider Prior to beginning NOAC therapy, patient's cognitive function, level of dependence, mobility, possible issues with drug compliance, and risk of falls must be assessed

Management of bleeding
The panelists of the advisory board also opined that CPs who are treating AF patients with oral anticoagulants (OACs) in case of a bleeding event should immediately stop the anticoagulant, look for potential drug-drug interactions, and refer the patients to a specialist.
The factor concentrates recommended for the management of bleeding due to NOACs include prothrombin complex concentrate (PCC) and activated PCC (aPCC) [13]. For the reversal of direct NOACs, the DCGI has approved one specific antidote: idarucizumab for dabigatran ( Figure 7). Evaluation of renal function should be considered annually or on a more frequent basis depending on medical history or age as per following EHRA recommendations ( Table 8) [13].

Patient type Interval
Patients other than those specified below Yearly  For patients with prior unprovoked bleeding, or experienced warfarin-associated bleeding, or are at a high risk of bleeding, the use of apixaban or dabigatran 110 mg has been recommended since less major bleeding events are associated with them as compared to warfarin [47].

Counseling
Patients starting on any OACs should be counseled and properly educated on compliance and precautions related to the therapy [48]. Patient counseling helps in ensuring adherence to the dosing schedule and regular follow-up. The panel on the advisory board discussed the importance of counseling and reached a consensus to develop a checklist that CPs can follow as counseling checkpoints (Figure 8).

Switching
Switching from one oral anticoagulant therapy to another is decided by the treating physician and is dependent on the patient's eligibility [49]. The major reason for switching from a VKA to a NOAC was occurrence of stroke. Occurrence of myocardial infarction or gastrointestinal bleeding after NOAC initiation significantly increased the chances of switching to VKA. The likelihood of switching from one NOAC to another increased in case of stroke, myocardial infarction, and gastrointestinal bleeding [50]. Ensuring continuous anticoagulant therapy with minimal bleeding risk is paramount while switching between therapies ( Figure 9) [13,44].