Potential use of NOACs in developing countries: pros and cons

Patients with non-valvular atrial fibrillation (NVAF) have a substantial risk of stroke and thromboembolism compared with age-matched people in sinus rhythm. This risk ranges from less than 1% to more than 20% per year depending on associated comorbidities and demographic characteristics (1). Thus, the prime challenge facing physicians caring for patients with NVAF is to identify patients at substantial risk for stroke and thromboembolism, and provide appropriate antithrombotic treatment whether as primary or secondary prevention. This has led to the development of stroke risk stratification schema, such as the CHADS2 score, whereby ‘high risk’ patients can be targeted for oral anticoagulation therapy; this is despite limitations of simple risk scores (2, 3). Until recently the vitamin K antagonists (VKAs) were the only orally administered agents able proven to lower the risk of stroke and mortality in patients with NVAF, although these benefits were balanced against small changes in the annual rate of major haemorrhage, including intracranial bleeding (4, 5). One recent ‘real world’ nationwide cohort analysis found that the net clinical benefit (balancing stroke against intracranial haemorrhage) was only negative for warfarin compared to no treatment in ‘truly low risk’ patients, defined using the ESC guidelines (1). Given the improvement in efficacy and safety with the new oral anticoagulants, the net clinical benefit is likely to be even greater. The absolute reduction in stroke risk attributable to oral anticoagulation highlights the effectiveness of anticoagulation, which is even greater amongst elderly subjects. Nonetheless, treatment with VKAs has important caveats. Indeed, the optimal anticoagulation intensity for patients with NVAF has been a subject of debate, although anticoagulation intensities with international normalised ratios (INRs) between 2.0 and 3.0 appear to provide the best protection from stroke and death, when balanced against the risk of bleeding (6, 7). Even with the optimal anticoagulation intensity established, keeping patients in the VKAs therapeutic range has not been an easy task. In general, implementation of evidence in practice has been proved slow and incomplete in the field of stroke prevention in AF. As a result, a large proportion of patients at high risk are either not treated or suboptimally treated with VKAs. Thus, it become crucial to evaluate the quality of anticoagulation and the time in therapeutic range (TTR) emerged as the most promising index. The TTR is the ratio of estimated duration of anticoagulation intensity within a pre-determined range to total duration, and Rosendaal et al. designed a method to calculate TTR based on the assumption that anticoagulation intensity shifts linearly between any two consecutive measurements (8). TTR is recognised as a marker of the quality of anticoagulation control in patients taking VKAs, and used to demonstrate the effectiveness of patient education and self-monitoring (9, 10). Moreover TTR has been used to appraise the quality of anticoagulation in the VKA arms of randomised clinical trials that evaluated the efficacy of novel antithrombotic drugs. In the latter setting it become apparent that even in the ideal environment of clinical trials the mean time spent in the therapeutic range rarely exceeds 65% (11). In the current issue of Thrombosis and Haemostasis, Gallagher et al. (12) evaluated the association between TTR and the risk of stroke and mortality, in a study cohort that included 37,907 AF patients from the UK General Practice Research Database. The large sample size allowed the authors to compare outcomes of VKA users with different percentages of time spent within therapeutic range. The authors concluded that good anticoagulation control was associated with a reduction in the risk of stroke versus no therapy, whilst TTR was a strong predictor of the risk of stroke. Indeed, poorer anticoagulation control was generally associated with a much larger risk of stroke (12). Previous studies have reported similar results regarding the importance of TTR on the outcome of VKA-treated patients with NVAF. For example, in an ancillary analysis of the ACTIVE W trial the benefit of anticoagulation compared with antiplatelet therapy was demonstrated only at medical centres where the average TTR was above 65% (the mean TTR for all patients in the study was 63.4%) (13). Similarly, a metaanalysis that included data from 21 studies and a total of 6,248 patients concluded that in patients with NVAF, the risk of ischaemic stroke with insufficient VKA anticoagulation (defined as INR 3) are significantly higher relative to patients with AF maintained within the recommended INR (14). Beyond the anticipated concluding remarks, the study by Gallagher et al. (12) has important unique points, including the use of data from the ‘real world’ practice. Until now, most data on the impact of TTR on the outcome of VKA-treated patients have come from the VKA arms of randomised clinical trials (15). Secondly, in this ‘real

Cancer patients face a four- to sevenfold higher risk of venous thromboembolism (VTE) than the general population. Novel oral anticoagulants (NOACs) provide convenient alternatives to traditional therapies. We performed a systematic literature search across PubMed, Embase, and the Cochrane Library, targeting studies that examined the use of NOACs in cancer-associated VTE. The search included randomized controlled trials (RCTs). Selected studies compared NOACs with low-molecular-weight heparin (LMWH) or vitamin K antagonists (VKA) in cancer patients diagnosed with VTE. A meta-analysis using a random-effects model was applied to estimate pooled effect sizes for outcomes. In this meta-analysis, we included 12 RCTs. Results showed NOACs were more effective than LMWH in preventing VTE recurrence (RR 0.66, 95% CI 0.52-0.83, p = 0.0004). Compared with VKAs, NOACs showed no significant difference (RR 0.63, 95% CI 0.34-1.15, p = 0.13). However, this finding is limited by the small patient sample. Major bleeding outcomes were similar between NOACs and LMWH/VKAs (RR 1.24, 95% CI 0.85-1.80, p = 0.28; RR 0.77, 95% CI 0.39-1.53, p = 0.46, respectively). Meta-regression analysis indicated a statistically significant positive correlation between mortality and major bleeding events when comparing NOACs with LMWH (p = 0.049). There was no significant difference in all-cause mortality between patients treated with NOACs and those treated with LMWH (RR 1.04, 95% CI 0.92-1.18, p = 0.54) or VKAs (RR 0.94, 95% CI 0.72-1.23, p = 0.65). Meta-analysis shows NOACs, especially factor Xa inhibitors, reduce VTE recurrence in cancer patients more effectively than LMWH. Comparison between NOACs and VKAs is inconclusive due to limited patient data. Further research is needed to assess NOACs' efficacy and safety against VKAs.

Background: Atrial fibrillation (AF) increases the risk of stroke and systemic embolism, necessitating anticoagulation therapy. Traditional vitamin K antagonists (VKAs) like warfarin have limitations, prompting the use of novel oral anticoagulants (NOACs), which offer advantages like predictable dosing and fewer interactions.Objective: To compare the effectiveness and safety of NOACs versus VKAs in AF patients.Methods: A comprehensive literature search was conducted across PubMed, Cochrane CENTRAL, EMBASE, Web of Science, and Scopus to identify randomized controlled trials (RCTs) and observational studies published between 2014 and 2024. Data were synthesized using a random-effects model, with subgroup analyses based on patient characteristics. The primary outcomes included stroke, systemic embolism, and major bleeding.Results: A total of 42 studies involving approximately 250,000 patients met the inclusion criteria. NOACs reduced the risk of stroke and systemic embolism by 19% (RR 0.81, 95% CI 0.75-0.87) and major bleeding by 16% (RR 0.84, 95% CI 0.79-0.90) compared to VKAs. NOACs also halved the risk of intracranial hemorrhage (RR 0.50, 95% CI 0.42-0.59).Conclusion: NOACs offer comparable or superior efficacy in stroke prevention with a better safety profile than VKAs, supporting their broader adoption in clinical practice for AF patients.

Introduction: Anticoagulants including warfarin and novel oral anticoagulants (NOACs) are recommended for stroke prevention in non-valvular atrial fibrillation (NVAF) patients. Limited data are available on real-world use of warfarin and NOACs in these patients since the entry of NOACs into the US market in October, 2010. Hypothesis: Warfarin and NOACs are prescribed for stroke prevention differentially based on patient characteristics. Methods: Incident cases of NVAF were identified from GE electronic medical records database between 11/2010 and 08/2011 based on ICD-9 codes 427.31 and 427.32. Baseline characteristics were obtained from medical record history prior to diagnosis. Patients were assessed over 6 months for initiation of warfarin or NOAC (dabigatran or rivaroxaban). Factors associated with anticoagulant initiation and NOAC initiation were examined using multivariate logistic regression analyses. Results: Among 19,730 NVAF patients, mean age was 70.8 years, 45.5% were female, and 36.5% initiated an anticoagulant (31.0% warfarin and 5.5% NOAC). CHADS2 score differed across treatment groups with CHADS2 ≥2 found in 47.9%, 45.6% and 36.3% of patients receiving warfarin, NOACs, and no anticoagulants, respectively (p < 0.001). Age, prescriber type, hypertension, diabetes, CHF, prior stroke/TIA, prior MI, and history of GI or other bleeding were significantly associated with the use of anticoagulants. NOAC use was more likely than warfarin in patients with hypertension (OR=1.19), history of GI bleeding (OR=1.40) and prior aspirin use (OR=1.81) but less likely in those with history of CHF (OR=0.70). Conclusions: Since the entry of NOACs, over 60% of newly diagnosed NVAF patients did not receive anticoagulants despite 36% of those patients having CHADS2 score ≥2. GI bleeding history, CHF, and prior aspirin use were major clinical factors associated with NOAC use. Further research is warranted to examine changes in anticoagulant treatment over time.

BackgroundNon-valvular atrial fibrillation (NVAF) is the most common cardiac arrhythmia in clinical practice, affecting nearly 1% of the general population.1 In Spain, the stipulated recommendations to select anticoagulant are: use...

In recent times, novel oral anticoagulants (NOACs)/direct oral anticoagulants (DOACs) have emerged as an alternative to the traditionally used VitaminK oral antagonists (VKA)like warfarin for the treatment of atrial fibrillation (AF). This systematic review and meta-analysis aims toevaluate the efficacy and safety of NOACs in patients with AF and, thus, the related thromboembolic risks and sequelae. Of the 131 published articles we examined, 11 were included in an in-depth systematic review. The articles we reviewed were from the past ten years, from 2013 onward. The analysis derived the efficacy and safety of NOACs in patients with AF and also included different patients' baseline characteristics and subgroups. This systematic review reiterates previous research findings of superior efficacy and safety of the use of NOACs in the AF population and also illuminates certain head-to-head comparisons of individual NOACs with warfarin.It digressed into subgroups of patients with different baseline characteristics to provide evidence and support the existing guidelines for the use of NOACs in the treatment of AF. Overall, there is marked efficacy and safety of NOACs in patients with AF, be they elderly or Asian, with decreased renal function, or with other comorbidities. Adherence to NOACs was also satisfactory. Despite such a review, there needs to be more research on vast subgroups and also on reversal antidotes like andexanet alfa and idarucizumab, as well as more head-to-head analysis between NOACs over a long duration of study, which would provide more answers and pinpoint reasons as to the differences that exist between demographics and subgroups in the usage of NOACs.

Background The life-span of patients with congenital heart disease strongly increased during the last decades due to advances in diagnostic and therapeutic approaches. Some cardiac malformations may involve an increased risk of thrombo-embolic complications. Further, adult patients with congenital heart disease (ACHD) are at increased risk to develop cardiac arrhythmia, such as atrial flutter or fibrillation. Therefore, various constellations may indicate anti-thrombotic and/ or anti-coagulative preventive or therapeutic regimen. Concomitantly, progress was made in the development of anticoagulative pharmacotherapy in the last decade with the development of the novel oral anticoagulants (NOACs). Purpose Aim of the study is to assess the use of oral anticoagulants, particularly of the NOACs dabigatran, rivaroxaban, apixaban, and edoxaban in ACHD in an unselected real-world scenario. Methods Data are derived from the German BARMER health insurance comprising approx. 9 million insurants. Within the years 2005 - 2017, we identified all adult patients that were hospitalized with a main or secondary diagnosis of a congenital heart disease by ICD-10 (Q20–28). Patients were categorized into simple, moderate, and high complexity cardiac lesions of heart disease. Oral anticoagulants were identified by ATC codes and assigned to the patient if prescribed at least twice. Results Overall, we included 13,344 ACHD patients (137,079 patient years). The use of oral anticoagulants increased from 8.3% in 2005, to 13.1% in 2010, 19.8% in 2015 and up to 22.5% of patients in 2017. Correspondingly, the use of vitamin K antagonists increased, reaching a plateau at approx. 14% since 2012. More interestingly, however, the prescription of NOACs constantly increased from 1.6% in 2012 to 8.4% in 2017. Therefore, NOACs were used for anticoagulation in 37% (n=802) of ACHD patients in 2017. Among those treated with NOACs, apixaban was used in 44.1% of patients, compared to rivaroxaban in 38.5%, edoxaban in 10.5% and dabigatran in 6.9%. With regard to heart disease complexity, oral anticoagulation was used in 21% ACHD with simple defects (1,065 of 5,080 patients), 19% of ACHD with moderate complexity disease (430 of 2,296), and 30% in complex ACHD patients (644 of 2,138). NOACs were applied to 6.2% of simple ACHD patients, 7.7% of ACHD patients with moderate complexity disease and 14.6% of complex ACHD patients. In 2017, 22.5% of ACHD (2,139) were anticoagulated. Thereof, Vit K ant. were used in 62.5%, apixaban in 16.5% and rivaroxaban in 14.4% (see figure). 2017: Use of oral anticoagulants in ACHD Conclusion Over 20% of ACHD patients require anticoagulation in the current era. Interestingly, despite the lack of prospective studies increasingly NOACs are replacing vitamin K antagonists in the ACHD population. In 2017 NOACs accounted for 37% of all anticoagulated patients in our study. The use of NOACs was not restricted to simple lesions but up to 30% of complex ACHD patients received NOACs in the current era.

Patients with non-valvular atrial fibrillation (NVAF) receiving vitamin K antagonists (VKAs) with time in therapeutic international normalized ratio (INR) range (TTR) <70%, despite good adherence, are by guidelines recommended to switch to non-VKA oral anticoagulants (NOACs). The aim was to assess if patients are switched from VKA to NOAC when TTR is <70% in a real-world setting. Non-valvular atrial fibrillation patients receiving VKA (1 January 2010 to 31 December 2012) were identified in nationwide registries. Time in therapeutic range was calculated by the Rosendaal method by a minimum of three INR values. Time in therapeutic range of patients continuing VKA (non-switchers) were compared with patients switched from VKA to dabigatran or rivaroxaban (switchers), the only NOACs available at that time. Factors associated with switching were analysed in a multivariable logistic regression model. 7276 patients with NVAF receiving VKA were included; of these, 6437 (88.5%) patients continued VKA [57.9% male, median age 76.7 years (Q1-Q3 68.9-83.5)] and 839 (11.5%) switched to NOAC [54.0% male, median age 76.5 years (Q1-Q3 68.4-83.6)]. No significant differences in CHA2DS2-VASc and HAS-BLED scores were seen between the groups. The mean TTR for non-switchers was 64.0 [standard deviation (SD) 27.8] and 52.9 (SD 28.1) for switchers. Among non-switchers, 51% had a TTR <70% vs. 69% among switchers. 85% of patients with TTR <70%, were not switched contrary to recommendations. Time in therapeutic range <70% was associated with the switch [odds ratio 2.28, 95% confidence interval (1.92-2.72)]. A TTR below 70% was associated with switching from VKA to NOAC, yet by guidelines, most patients were still not switched.

Patients with chronic kidney disease (CKD) are at increased risk of atrial fibrillation, stroke, and bleeding posing unique clinical challenges. Novel oral anticoagulants (NOACs) including dabigatran, rivaroxaban, and apixaban have become recognized as alternative therapy to Vitamin K Antagonists (VKA) regarding the prevention of venous thromboembolism (VTE) and reduce the risk of stroke in atrial fibrillation. However, the understanding of NOACs in CKD is still underdeveloped. This review summarizes recent literature on the efficacy and safety of NOACs in patients with CKD. Studies focusing on patients with moderate kidney disease were drawn from post hoc analyses from three major NOAC trials, meta-analyses, and postmarketing surveillance studies. Cumulatively, these studies continue to demonstrate NOACs as equivalent if not superior therapies to VKAs in regards to both efficacy and safety. These studies are limited by small sample sizes as well as a lack of direct comparison between NOACs. The role of NOACs in managing VTE and atrial fibrillation is increasing. Current research suggests that NOACs are at least as efficacious and well tolerated as VKAs. More research is required to elucidate which NOAC is preferable in the clinical setting.

BackgroundNon-valvular atrial fibrillation (NVAF) is the most common cardiac arrhythmia in clinical practice, affecting nearly 1% of the general population1.Anticoagulation therapy with vitamin K antagonist (VKA) is a treatment used...

The outcomes of postmarketing studies on a novel drug are often less favourable than those of the drug's phase III trials. Several causes underlie this discrepancy—often methodological by nature, many of which may be unavoidable. However, one avoidable caveat is overlooked too often: if participants of phase III trials differ markedly from the patients who will receive the drug, it may take years before all the clinical effects of the drug are properly known. New postmarketing studies have shown that this is arguably the case for dabigatran, a novel oral anticoagulant (NOAC) used to prevent ischaemic stroke in patients with non-valvular atrial fibrillation (NVAF). Currently, physicians treating patients with NVAF are faced with an important decision; whether to prescribe traditional oral anticoagulants, in the form of vitamin K antagonists (VKAs) like warfarin, or to start with an NOAC. The focus of our paper is on dabigatran, a direct thrombin inhibitor, because it was the first NOAC that appeared on the US market in 2010, and is the most prescribed and most thoroughly researched NOAC thus far.1 However, the discussion presented here may also apply to the other NOACs currently on the market (the direct factor Xa inhibitors Apixaban, Edoxaban, and Rivaroxaban). Results from the phase III trial on dabigatran, called the RE-LY trial, suggest that dabigatran 150 mg b.i.d. is more effective in preventing ischaemic stroke than VKAs, with a lower risk of intracranial haemorrhage.2 Dabigatran 110 mg b.i.d. is found to be equally effective as VKAs in the RE-LY trial, with less bleeding complications. However, this dose has not been approved for the USA. Although the results from the RE-LY trial were positive, it is questionable whether dabigatran is the best option for stroke prevention in some or even many NVAF patients. A recently published postmarketing study … [↵][1]*Corresponding author. Tel: +31 24 366 8171, Fax: +31 24 361 3505, Email: herbert.rolden{at}radboudumc.nl [1]: #xref-corresp-1-1

Left atrial ablation strategies are being increasingly performed as a Class 1 therapeutic indication for drug refractory paroxysmal atrial fibrillation (AF). Traditionally AF ablation has been performed with patients on uninterrupted warfarin therapy, however over the last few years, novel oral anticoagulants (NOACs) have emerged as attractive alternatives to warfarin in order to reduce stroke risk due to AF. NOACs are therefore increasingly being used instead of warfarin in the management of AF. There is also mounting evidence mainly in the form of small randomised studies and meta-analysis that have demonstrated that the use of NOACs for AF ablation is efficacious, safe and convenient. However the peri-procedural dosing protocols used in various studies especially in terms of whether NOAC use is interrupted or uninterrupted during AF ablation, have significant inter-operator and inter-institution variability. Currently there is also a lack of randomised controlled trials to validate the data obtained from meta-analyses. There is also evidence that use of NOACs may increase the requirement of unfractionated heparin during the procedure. This review article shall examine the currently available evidence-base, appraise the gaps in the current evidence and also underscore the need for larger randomised clinical trials in this rapidly developing field.

Atrial fibrillation (AF) is a common heart rhythm disturbance; its incidence increases with age, and it is also an independent risk factor for stroke. Anticoagulation has been proven as the most effective way to reduce the risk of stroke in patients with AF, and vitamin K antagonists have been used for decades as the gold standard treatment. Vitamin K antagonists have a narrow therapeutic window in addition to variable pharmacokinetics and pharmacodynamics, and they frequently interact with food and other drugs, requiring coagulation monitoring to ensure balance between safety and efficacy. The novel oral anticoagulants (NOACs) dabigatran, rivaroxaban, apixaban, and edoxaban selectively target either thrombin or Factor Xa and have predictable pharmacologic profiles, removing the need for routine coagulation monitoring. This article summarizes phase III data in patient subtypes and discusses controversies surrounding AF management with these agents. Results indicate that NOACs in non-valvular AF have an overall improved efficacy–safety profile compared with warfarin. Significantly fewer fatal bleeding events were observed in patients randomized to rivaroxaban, apixaban, or edoxaban compared with those on warfarin, and significant reductions in the incidence of life-threatening bleeding were observed in patients randomized to dabigatran. All four pivotal trials testing the NOACs against warfarin showed significantly lower rates of intracranial bleeding in patients administered NOACs. These results suggest that wider use of NOACs has the potential to improve outcomes for most patients with AF.

Comparison of prevalence and management of left atrial appendage thrombi under old and new anticoagulants prior to left atrial catheter ablation

Direct oral anticoagulants (DOACs) are widely used in patients with atrial fibrillation and venous thromboembolism. The lack of the need for laboratory monitoring and a better safety than vitamin K antagonists (VKAs) has probably changed the quality of life of patients on these oral anticoagulants. This was a real-life prospective observational cohort study. The aim was to evaluate if a long-term treatment with DOACs could offer a better quality of life than VKAs. Moreover, age, gender, education level, time in therapeutic range for VKAs, taking medication once or twice a day for DOACs, the total daily number of medications and thrombotic and bleeding complications were considered as variables probably associated with the quality of life of these patients. Between January and December 2021, the Duke Anticoagulation Satisfaction Scale (DASS) 25-items was administered as an interview to patients on either VKAs or DOACs therapy. During the follow-up period, all of the patients were closely monitored to evaluate possible bleeding and thrombotic events. The analysis included 300 outpatients treated with VKAs and 254 treated with DOACs. In general, the quality of life was better in patients taking DOACs (DASS total score: DOACs = 44.7, 42.9-46.5 vs. VKAs = 51, 49.2-52.8, p < 0.0001) as the daily-life limitations, hassles and burdens and the psychological impact were less important than in patients on VKAs therapy. VKAs negatively influence the daily-life of the patients in terms of both less satisfaction and time-consuming tasks. DOACs confer a better quality of life even if some concerns emerge from not knowing how their therapy is working.