**8. Current recommendations - Caution**

better in the Asian population and whether they may be due to different effectiveness of the drug in this population or whether there was any element related to the study design to jus‐ tify these differences. In addition 35% of patients with warfarin were outside the therapeutic

In the RE-LY treated with warfarin branch has an open design which favors the appearance of bias. It would be necessary to make a double-blind design with warfarin (this limits the internal validity of the test. Both the ROCKET AF as ARISTOTLE was double blind). Dabi‐ gatran is necessary to take it twice a day. This helps to foster low compliance. Only in the RE-LY study, where patients are monitored closely, the dropout rate was 20.7% with dabi‐ gatran 110 mg and 21.2% with dabigatran 150 mg at two years. The same can happen with rivaroxaban and apixaban, the absence of regular checks can relax patients. Poor adherence to treatment would leave the patient exposed because the anticoagulant effect almost com‐ pletely disappear (are drugs with short half-life). Unlike NOACs, with VKAs is necessary to periodically checks to confirm that are within the therapeutic range, a fact that is achieved in 58-65% of cases. The compliance rate is not always the desired (30% dropout) [37]. A sub‐ group analysis and an FDA report further notes that the benefit of dabigatran is significant only in those centers where patients have poorer control with warfarin. The results of the centers with better INR control with warfarin did not show superiority of dabigaran 150 mg versus warfarin. Improving the monitoring of the INR, the benefits seen for dabigatran com‐ pared to warfarin decreased. The ARISTOTLE study showed no superiority of apixaban in terms of INR control. The ROCKET AF study the level of INR of warfarin group was very low which has reduced the conviction to conclusions (55% versus 64.4% of RE-LY and 62%

Regarding the dose to be administered there are disputes between the position of the FDA (Food and Drug Administration) and EMEA. FDA has approved only high doses of dabiga‐ tran (150 mg/12h). Argued that low doses of dabigatran (110 mg/12h), the demonstration of non-inferior to warfarin, is not as conclusive as with higher doses. In addition to high doses reduces episodes of stroke but increase bleeding. The lower dose may be indicated in pa‐ tients with increased risk of bleeding. The RE-LY study could not identify a subgroup of pa‐

Recently has been published a study that try to perform an indirect comparison analysis of NOACs regarding its efficacy and safety [36]. Despite the limitations of indirect comparison study (differences in patient population, differences in definition of major bleeding and un‐ blended versus nonblinded/double-blinded comparisons), no profound significant differen‐ ces were found in efficacy between apixaban and dabigatran (both doses) or rivaroxaban. Dabigatran 150 mg twice daily was superior to rivaroxaban for efficacy (with less stroke and systemic embolism (by 26%), as well as less hemorrhagic stroke (by 56%, p=0.039 and non‐ disabling stroke (by 40%, p=0.038). There were no significant differences in preventing stroke and systemic embolism for apixaban versus dabigatran (both doses) or rivaroxaban, or rivaroxaban versus dabigatran 110 mg twice daily. For the ischemic stroke, there were no significant differences between the NOACs. Major bleeding was significantly lower with apixaban versus dabigatran 150 mg twice daily (by 26%) and rivaroxaban (by 34%), but was

range, implying poor control within the clinical trial.

220 Atrial Fibrillation - Mechanisms and Treatment

of ARISTOTLE).

tients who would benefit from low dose.

With the entry into force of the NOACs is emerging a new era in anticoagulant therapy. These drugs are proving to be at least as effective as VKAs without coagulation monitoring, with a reduction of more serious bleeding (intracranial) and with far fewer potential drug interactions and food.

But not all advantages. These drugs also have drawbacks and uncertainties about their safe‐ ty, and to their clinical evaluation is needed before definitive recommendations on its use. Lack of specific antidotes which is a problem in patients who are at high risk of bleeding or hemorrhage (to negate the effect is included prothrombin complex or factor specifying of hospitalization and increasing costs associated with treatment), contraindicated in patients with renal impairment, short half-life (limits its use in patients with poor adherence), with higher incidence of gastrointestinal bleeding and high cost. In addition, there are no safecy data long-term selected populations and are generating security alerts.

In the initial euphoria, with the placing on the market NOACs, it is necessary to proceed with caution. A few years ago, another promising thrombin inhibitor, ximelagatran, which showed that it was at least as effective and safe as warfarin for stroke prevention in AF pa‐ tients, had to be withdrawn by its liver toxicity after creating many expectations [41].

The experience of use and new studies will determine the profile of patient who may benefit most from these new therapies. Be taken into account: stage of disease, the left atrial size, presence and severity of underlying disease, therapeutic approaches and patient preferen‐ ces. It also assessed the patients' age, presence of comorbidities and polypharmacy. Ad‐ vanced age increases the impact of AF on the embolic risk. The elderly population is particularly vulnerable to stroke in AF. In addition, stroke patients with AF have increased

New Oral Anticoagulants in Atrial Fibrillation

http://dx.doi.org/10.5772/53614

223

Clinical trials available to date show that NOACs are at least as effective and safe as VKAs. However, although the evidence is a useful tool, it should await the development of major clinical studies in different populations to see the real benefit of these drugs. The main prob‐ lems are lacking proven methods of monitoring, so that in certain patients (elderly, low weight, renal or liver impairment...) fixed dose may not be therapeutic. There are no conclu‐ sive data on its long-term safety and are already generating security alerts in different coun‐ tries. No studies support the use of an antidote in case of overdose with bleeding. There is no justification to replace the current oral anticoagulant treatment by the NACOs in patients that conventional treatment is well tolerated and its controls are stable. Its high cost limits the use of these drugs. Independent trials are needed to precisely define the role of new

mortality and the consequences are devastating.

drugs in patients with non-valvular AF.

and José López-Castro2

1 Department of Pharmacy, Hospital Comarcal Valdeorras, Sergas, Spain

Not have any conflict of interest relating to the information in this article.

2 Department of Internal Medicine, Hospital Comarcal Valdeorras, Sergas, Spain

[1] Fuster V, Rydén LE, Cannom DS, Crijns HJ, Curtis AB, Ellenbogen KA, et al. ACC/AHA/ESC 2006 Guidelines for the Management of Patients with Atrial Fibrilla‐ tion: A report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines and the European Society of Cardiology Commit‐ tee for Practice Guidelines (Writing Committee to Revise the 2001 Guidelines for the Management of Patients With Atrial Fibrillation): Developed in collaboration with

**9. Conclusions**

**Author details**

Lucía Cid-Conde1

**References**

All this raises questions: Is it appropriate to change oral anticoagulation with warfarin or acenocoumarol to a patient controlled? Can these NOACs impact in preventing throm‐ boembolism, especially stroke, in patients with AF? Will we monitor patients? Is it accepta‐ ble despite the cost of not requiring monitoring? How do we assess adherence?

The Canadian Cardiovascular Society (CCS) [41], the European Society of Cardiology (ESC) [13,42,43], the American College of Cardiology Foundation (ACCF), the American Heart Asso‐ ciation (AHA) and the Heart Rhythm Society (HRS) recently updated their guidelines for the treatment of patients with AF. The guidelines report that when OAC is recommended, one of NOACs should be considered rather than adjusted-dose VKAs (INR 2.0-3.0) for most patients with AF, when studied in clinical trials to date. The NOACs provide better efficacy, safety and comfort compared to the OAC with VKAs. There is insufficient evidence to recommend one over another NOACs, although some patient characteristics, drug tolerability and compliance and the cost may be important factors in the choice of agent. As experience with NOACs is still limited, strict adherence to the recommended indications approved and aftercare marketing.

The short half-lives of NOACs compared with that do not require routine monitoring of coagu‐ lation, causes adherence is very relevant. Poor adherence increase morbidity, mortality, and in turn, overall health costs. Poor compliance can be a particular problem in patients with AF who often has no symptoms. Warfarin has a half life of 40 hours, so that a slight failure of the patient will have a negligible effect on clotting compared to a drug with short half life.

In this context it is useful to provide a meta-analysis of clinical trials in patients treated with VKAs. The results showed that patients who achieved a treatment well stabilized, the deter‐ mination home ("self") for the same patient resulted in a significant reduction in mortality and morbidity from thromboembolism without increasing the risk of serious bleeding in a selected group of motivated adults [44]. The results of a subsequent meta-analysis showed a reduced risk of thromboembolic disease, but no major bleeding or mortality [45].

The NOACs will not replace the classical therapy of oral anticoagulant therapy automatical‐ ly. As a general rule, you should not change the anti-clotting drug to patients who are cur‐ rently well controlled with acenocoumarol or warfarin and have an INR within the therapeutic range. The NOACs be reserved for those who have not attained regular values (between 2.0 and 3.0) the INR by more than 60% of the determinations despite good adher‐ ence to the prescription by the patient (for drug interactions that hinder the anticoagulation control, special dietary or digestive disorders that affect the pharmacokinetics of VKAs. Should not switch to dabigatran in patients with inadequate control of INR and nonadher‐ ence) [46], for those with mobility problems or difficulties traveling to determine the INR and for which have allergies or intolerance to the adverse effects of OACs. An anticoagulant is, by definition, a drug of high risk. And a patient with AF generally well. The fact that new drugs is involved uncertainty about their safety in the short and long term. You have to de‐ fine more precisely the role of new drugs, considered as therapeutic innovations, and they are accompanied by a careful evaluation of their efficacy and toxicity in actual practice.

The experience of use and new studies will determine the profile of patient who may benefit most from these new therapies. Be taken into account: stage of disease, the left atrial size, presence and severity of underlying disease, therapeutic approaches and patient preferen‐ ces. It also assessed the patients' age, presence of comorbidities and polypharmacy. Ad‐ vanced age increases the impact of AF on the embolic risk. The elderly population is particularly vulnerable to stroke in AF. In addition, stroke patients with AF have increased mortality and the consequences are devastating.
