Introduction
One of the commonest arrythmia in clinical practice is Atrial fibrillation (AF) and it is estimated that about 1% of the population suffer from AF worldwide.1 AF could be of valvular origin, typically rheumatic heart disease, but the vast majority of cases are of nonvalvular etiology. The risk of stroke secondary to either permanent or paroxysmal AF is the same and, should be treated in the same manner from the perspective of thromboprophylaxis.2 AF is responsible for 15% of ischemic strokes overall, and in elderly it rising up to 25%.3 Thromboprophylaxis is critical for the prevention of strokes in patients with AF (SPAF). Until recently, vitamin K antagonists (VKAs; e.g. warfarin & Acenocoumarol) and aspirin have been widely used to manage the risk of ischemic stroke in patients with AF. The VKAs are highly effective in stroke prevention; for example, well-controlled warfarin treatment can reduce the risk of ischemic stroke and systemic embolism by up to two-thirds and is associated with a 26% relative risk reduction in all-cause mortality in patients with nonvalvular AF.4
About 60% of patients never get VKA, around half of patients who do get it stop taking it especially in the developing world, and of those who still take it only half are in therapeutic range. So, only a small percentage of patients are well treated.5
The use of warfarin and Acenocoumarol in clinical practice is challenging due to problems such as a narrow therapeutic index and unpredictable anticoagulant effects, drug-drug and drug-food interactions, all of which result in the need for regular laboratory monitoring (PT/INR). So there is need to develop an effective oral anticoagulant with reliable pharmacokinetic profile so can be taken as fixed daily dosage, regardless of patient’s age, weight, ethnicity or gender.
The non-VKA oral anticoagulants (NOACs like Dabigatran, Rivaroxaban, Apixaban) have changed the landscape of thromboprophylaxis for SPAF by offering physicians and patients the opportunity to use effective anticoagulants with predictable pharmacokinetic profiles, fewer drug– drug and drug–food interactions without the need for PT / INR monitoring and wide therapeutic windows.
Two classes of NOACs have been developed, and 3 drugs are currently licensed for use as anticoagulants in nonvalvular AF. The direct thrombin inhibitors (dabigatran) and the direct factor Xa inhibitors (rivaroxaban and apixaban).
In 2010, dabigatran etexilate, was approved for stroke prevention in non-valvular atrial fibrillation, marking the advent of a new age in anticoagulation. Prior to the development of dabigatran, efforts to develop a non-vitamin K antagonist (VKA) oral anticoagulant had been disappointing. The first such drug, ximelagatran, was never approved for use in the United States (US) after completion of phase 3 trials in VTE prevention and treatment due to hepatotoxicity.6
All four NOACs have been found to be noninferior to warfarin for the prevention of stroke and systemic embolism in large, international randomized control trials.
Till today, there is no evidence to demonstrate that any of the NOACs are superior to the others for the prevention of stroke in AF (SPAF). Indirect comparison between the NOACs is made tough by subtle differences between the patient cohorts enrolled in the randomized trials.7
Table 1
Oral anti-coagulant available in India.
|
Vitamin K Antagonist |
Non-vitamin K antagonists |
|
Acenocoumarin (Acenocoumarol) |
Direct thrombin inhibitor |
|
Warfarin |
Dabigatran |
|
|
Factor Xa inhibitor |
|
|
Rivaroxaban |
|
|
Apixaban |
Table 2
Table 3
Results from pivotal phase 3 trials of four new anticoagulants8
Table 4
Key efficacy and safety outcomes of NOAC randomized controlled trials compared with warfarin 8
Table 5
Choosing the precise anticoagulant for SPAF
Complications, convenience, Compliance, confidence & cost are the 5 Cs for effective anticoagulation management.11 There are two important decisions that must be made with respect to anticoagulation in AF. First, should a patient with AF required anticoagulant treatment for thromboprophylaxis and, secondly, which anticoagulant should be used.
As per 2020 ESC Guidelines for the diagnosis and management of atrial fibrillation, Oral Anticoagulant (OAC) is recommended for stroke prevention in AF patients with CHA2DS2-VASc score ≥ 2 in men or ≥ 3 in women (Class I and level A evidence). Antiplatelet therapy alone (monotherapy or aspirin in combination with clopidogrel) is not recommended for SPAF. SPAF patients who are eligible for OAC, NOACs are recommended in preference to VKAs (excluding patients with mechanic al heart valves or moderate-to-severe mitral stenosis) (Class I and level A evidence). If a VKA is used, a target INR of 2.0 - 3.0 is recommended, with individual TTR ≥70%. (Class I & level B evidence).12
Which anticoagulant class to choose: VKAs or NOACs?
In India, Vitamin K antagonists are widely used oral anticoagulants. Vitamin K antagonists (VKAs) such as warfarin & Acenocoumarol have long been the mainstay of stroke prevention in patients with atrial fibrillation (AF). Nevertheless, the use of VKAs in clinical practice is always challenging due to problems such as drug-drug and drug-food interactions, a narrow therapeutic index and unpredictable anticoagulant effects, all of which result in the need for regular laboratory monitoring only advantage is cost of therapy.11 As per ESC 2020, If a VKA is used, a target INR of 2.0 - 3.0 is recommended, with individual TTR ≥70% which is extremely challenging in clinical practice. In a systemic review, Wan et al. found that poor control of anticoagulation associated with increased bleeding and thromboembolic risk. Indeed, it has been shown that when TTR falls below 50%, stroke outcomes are worse than if the patient remained untreated, and bleeding risk is higher.13, 14
Which NOAC to Choose?
Direct comparison of the results from large, international, multicentre randomized control trials of NOACs versus warfarin for SPAF is difficult due to differences in the mean CHADS2 score, TTR and rates of stroke and systemic embolism and haemorrhage in the warfarin arms of the trials.
Factors to considered while selecting appropriate NOACs
Medical conditions like renal & liver function, concomitant medications, age of patient, adherence and patient preference, patient at very high risk of ischemic stroke, patient with very high risk of bleeding & cost of therapy should be considered while selecting NOACs.
Patients With Renal Impairment
Renal impairment is related with an increased incidence of stroke (secondary to co-existent risk factors) and is an independent risk factor for haemorrhage (HR 1.27, 95% CI 1.09–1.49).15 Both the incidence of AF and renal impairment increase with advancing age; therefore, determining suitable and safe anticoagulation for this growing population is an important clinical issue.
VKAs have a poor safety profile in patients with non-dialysis dependent severe chronic kidney disease [estimated glomerular filtration rate (eGFR) <30], with these patients at a higher risk of major bleeding events and stroke compared to individuals with moderate renal impairment (eGFR 30–60) or compared to individuals with moderate renal impairment (eGRF 30– 60 ) or those without chronic kidney disease (eGFR > 60).16 Limited data on the safety and efficacy of NOACs in patients with AF and renal impairment are available.
Dabigatran has the greatest extent of renal elimination (80%), while 35%, and 27% of rivaroxaban, and apixaban, respectively, are cleared via the kidneys.
There are no data on the use of NOACs in AF patients after kidney transplantation. NOACs are used in such patients, the dosing regimen should be selected according to the renal function, and caution is needed concerning possible Dru Drug interaction between the NOAC and concomitant immunosuppressive therapies.17
Elderly Patients
The prevalence of AF is estimated to be between 10.0% and 17.8% in patients over the age of 85. The prevalence of AF rises with age.18, 19 Meta-analysis of the trials involving dabigatran, rivaroxaban and apixaban showed that NOACs were more effective than warfarin therapy in the SPAF; individual drugs were all found to be noninferior to warfarin in the elderly. NOACs were not associated with increase in major or clinically relevant bleeding events in patients over 75 years of age.20
Patients with high risk of haemorrhage
The HAS-BLED score can be used to predict the risk of haemorrhage, with a score of 3 or greater signifying significant risk. Compared to warfarin, each of the NOACs reduces the incidence of intracranial haemorrhage. Patients at high risk of gastrointestinal haemorrhage, it is reasonable to avoid high-dose dabigatran and rivaroxaban. In patients with high HAS-BLED scores who have suffered major haemorrhage, low-dose dabigatran, apixaban are all suitable choices of anticoagulant, but the risk of haemorrhage should be balanced carefully against the risk of stroke and patients’ personal preferences.4 BID dosing of NOACs like apixaban and Dabigatran causes lower peak–trough ratio of blood levels (i.e., lower peaks and higher troughs), compared with once a day dosing. Rivaroxaban had higher overall rates of GI Bleed (3.2 vs. 2.5 events per 100 person-years; hazard ratio [HR], 1.42 [95% CI, 1.04 to 1.93]) and major GI Bleed (1.9 vs. 1.4 events per 100 person-years; HR) compared with apixaban. Dabigatran was linked with lower rates of upper GI Bleed than rivaroxaban.21
Patients with existing coronary artery disease (CAD) or peripheral vascular disease
AF with CAD or PVD often co-exist. There is considerable scope for the overlap of anticoagulant & antiplatelet treatments in patients with CAD or peripheral vascular disease and concurrent AF. Single and dual antiplatelet therapies provide first line treatments for patients with coronary artery disease (CAD) or peripheral artery disease (PAD).4
In all four trials comparing NOACs to warfarin (VKA) in patients with AF, concurrent aspirin use was associated with higher incidence of major haemorrhage regardless of the treatment arm. The occurrence of major haemorrhage when a NOAC was co-administered with aspirin was consistently lower than that seen with warfarin. NOACs offer promising safety advantages compared to warfarin when used in combination with antiplatelet therapy, but this must be confirmed in future studies.4
Patients with a high risk of stroke or a previous TIA/stroke
A recent meta-analysis of the ROCKET-AF, RE-LY, and ARISTOTLE trials demonstrated that rivaroxaban, dabigatran, and apixaban were all noninferior to warfarin in this respect. Apixaban was associated with the lowest risk of stroke or systemic embolism in patients who had already suffered a previous stroke or TIA although this finding was not statistically significant.22
Availability of reversal agents
One of the important advantages of VKAs over NOACs is availability of reversal agent. Recently idarucizumab, a humanized monoclonal antibody fragment approved and available which binds and is an effective reversal agent for dabigatran.23 NOACs are having shorter half-lives compared with VKAs, meaning the requirement for reversal is likely to be less with NOACs than with VKAs.
Conclusion
Recent development of newer-generation, direct oral anticoagulants have been clinically authenticated to help overcome shortcomings of VKA therapy. These medications largely have a more consistent pharmacokinetic profile allowing once- or twice-daily administration without routine PT /INR monitoring. Less Drug-drug interactions. Mechanisms of action of DOACs directly inhibit different portions of the coagulation cascade. Dabigatran functions by direct inhibition of thrombin. Rivaroxaban, apixaban inhibit factor Xa. Selecting and adhering to anticoagulant therapy remains challenging for physicians and patients with AF.
