**7. Evaluation of scientific evidence, relevance and limitations of the study**

It will analyze the scientific evidence, the limitations of design and the clinical relevance of the results of published clinical trials (RE-LY, ROCKET AF, AVERROES and ARISTOTLE). In general, these new drugs are at least equally effective and safer than warfarin, with the advantage of inducing a lesser extent intracerebral hemorrhages (Table 6).


**Table 6.** Summary of the main clinical trials with NOACs

dure, it is important to note that the drug half-life (12-14 hours dabigatran, rivaroxaban 9-13 hours and apixaban 9-14 hours). If the invasive procedure has a low bleeding risk, it is suffi‐ cient to suspend the drug 24-36 hours before surgery and if no complications arise, resume

The ideal test for monitoring of direct thrombin inhibitors is the coagulation time of ecarin, with a linear relationship, and a good slope and discriminate levels of dabigatran in plasma.

The studies suggest that dabigatran monitoring will be done with a variant of thrombin time (TT). TT is very sensitive, with a linear relationship, but with a high slope, so that at low concentrations of dabigatran, TT extends above the detection limit of the coagulometer. It is a very good from a qualitative point of view, to assess adherence to treatment, but cannot quantify levels. The thrombin time will be a diluted thrombin time, marketed as Hemoclot®, which manages to improve the linear relationship with respect to TT and discriminate be‐

Monitoring of rivaroxaban will be done by a method chromogenic anti-factor Xa. This test is marketed as anti-Xa assay. Is a sensitive and accurate, useful to measure the maximum and

The fear of bleeding complications is one of the most prevalent obstacles in anticoagulant

These drugs have no specific antidotes which is a problem in patients who are at high risk of bleeding or hemorrhagic. Dabigatran is a dialyzable drug, which can eliminate up to 60% of the molecule in serum. Other possibilities include the use of activated coal and of neutraliz‐ ing antibodies but are lacking in vivo experience. With respect to rivaroxaban is working in a variant of factor Xa would compete with the normal to factor Xa when joining rivaroxaban

In order to reverse the effect of NOACs designed a crossover trial, randomized, doubleblind, placebo-controlled study included 12 healthy male volunteers. Received rivaroxaban 20 mg/12h or dabigatran 15 mg/12h for 2.5 days followed by a single bolus of 50 IU/kg of prothrombin complex concentrate (PCC) or similar volume of saline. The results concluded that the PCC completely and immediately reversed the anticoagulant effect of ribaroxaban but had no influence on the effect of dabigatran at the doses used in this study. These results should be analyzed with caution due to small sample size (12 patients) and the characteris‐ tics of the population that was part of the study (only male patients and healthy). [27]. An‐ other study found the low doses of non-specific reversal agents (anticoagulant anti-inhibitor complex with non-activated factors II, IX and X and activated factor VII) appear to be able to reverse the anticoagulant activity of rivaroxaban or dabigatran. However, clinical evaluation is needed regarding haemorrhagic situations, and a meticulous risk-benefit evaluation [28]. The absence of normalization of coagulation tests not necessarily correlate with the absence

of anti-haemorrhagic effect, as demonstrated in animal models [24].

The problem is that it is non-standardized and few laboratories possess it.

tween low, intermediate and high dabigatran in plasma [24].

minimum plasma concentrations of rivaroxaban [25,26].

**6. Bleeding complications and antidotes**

treatment in AF, especially cerebral hemorrhage.

and thus the effect would be reversed.

anticoagulant treatment at 36-48 hours [23].

214 Atrial Fibrillation - Mechanisms and Treatment

#### **7.1. Dabigatran**

The RE-LY is the largest study of AF (Randomized Evaluation of Long term anticoagu‐ lant therapy) [29]. The primary endpoint was to establish non-inferiority of dabigatran etexilate compared with warfarin for a minimum of 1 year follow-up to a maximum 3 years, median follow-up of 2 years in 18.113 patients with nonvalvular AF (mean age 71 years) with at least one of the following risk factors for stroke: previous stroke or transi‐ ent ischemic attack, left ventricular ejection fraction <40%, symptoms of heart failure class 2 or higher NYHA, age >75 years or 65-74 years associated with diabetes mellitus, hypertension or coronary artery disease. Meanwhile, we excluded patients with: severe valvular disease, recent stroke, (a condition that increases the risk of bleeding), CrCl <30mL/min, active liver disease and pregnancy.

were categorized as critical if they met one or more of the following criteria: fatal bleeding, symptomatic intracranial bleeding, reduced hemoglobin of at least 5g/dL, transfusion of at least 4 units of whole blood or packed red cells, bleeding associated with hypotension re‐ quiring the use of intravenous inotropic agents, bleeding required surgery) of 2.71% for da‐ bigatran 110 mg, 3.11% for dabigatran 150 mg and 3.36% for warfarin. No significant difference in major bleeding between dabigatran 150 mg twice daily and warfarin; on the contrary, dabigatran 110 mg twice daily resulted in less major bleeding, RR 0.80 (95% CI: 0.69 to 0.93) p = 0.003. As for minor bleeding (defined as all non-major bleeding definition, previously expressed) annual rates were 13.16%, 14.84% and 16.37% for dabigatran 110 mg, dabigatran 150 mg and warfarin, respectively. In this case, the risk was significantly lower for dabigatran 110 mg [RR = 0.79 (95% CI: 0.74 to 0.84)] and dabigatran 150 mg [RR = 0.91 (95% CI: 0.85 to 0.97)] with respect to warfarin and was higher for dabigatran 150 mg versus dabigatran 110 mg [RR = 1.16 (95% CI: 1.08 to 1.24)]. Similarly, the risk of intracranial hemor‐ rhage was significantly lower for dabigatran 110 mg [RR = 0.31 (95% CI: 0.20 to 0.47)] and for dabigatran 150 mg [RR = 0.40 (95% CI: 0.27 to 0.60)] against warfarin and no significant differences between the two doses of dabigatran. However, the risk of bleeding severe gas‐ trointestinal was significantly higher in the group treated with dabigatran 150 mg versus warfarin [RR = 1.50 (95% CI: 1.19 to 1.89)] and versus dabigatran 110 mg [RR = 1.36 (95% CI: 1.09 to 1.70)]. The overall mortality (4%) showed no significant differences (p=0.051) be‐ tween dabigatan 150 mg twice daily and warfarin, although the rate of deaths from vascular causes was significantly lower in the group treated with dabigatran 150 mg twice daily

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The results of dabigatran 150 mg dose showed that the benefit is somewhat larger than war‐ farin in CHADS2≥ 2 while the hemorrhagic risk is similar in both groups. In CHADS2 = 0-1 the benefit is also somewhat higher than warfarin while the hemorrhagic risk is somewhat lower. A dose of 110 mg the benefit and bleeding risk is similar in every category of

Dropout rates were higher with dabigatran: 14.5% with dabigatran 110 mg, 15.5% with 150 mg dabigatran and 10.2% with warfarin the first year and 20.7% with dabigatran 110 mg, 21.2% with dabigatran 150 mg and 16.6% with warfarin the second year. There were more withdrawals due to serious adverse events with dabigatran (2.7%) than with war‐

The incidence of myocardial infarction was higher with dabigatran 110 mg twice daily (0.72%, p = 0.07) and dabigatran 150 mg twice daily (0.74%, p = 0.048) than warfarin (0.53%), having calculated that myocardial infarction could occur for every 500 patients treated with dabigatran. With the correction of the results of RE-LY study the differentiation in the appa‐ rition of the myocardial infarction no longer statistically significant. However, a meta-analy‐ sis of 7 trials published recently concluded that the use of dabigatran is associated with an increased risk of myocardial infarction or acute coronary syndrome in a broad spectrum of patients compared with VKAs, antiplatelet or placebo [30]. Although the absolute risk may be low, it is necessary to closely monitor patients and the importance of improving pharma‐

CHADS2 except for the category CHADS2 = 0-1 where the risk is somewhat lower.

(p=0.04).

farin (1.7%).

covigilance systems [31]*.*

Patients were randomized into three treatment arms: 110 mg dabigatran twice daily, dabiga‐ tran 150 mg twice daily and adjusted dose warfarin (INR 2.0-3.0). In patients randomized to receive warfarin, the average percentage of time within therapeutic range (INR = 2.0-3.0) were 64.4%. Dabigatran was administered in a blinded fashion in both treatment arms; the administration of warfarin was opened. In all branches were allowed concomitant use of acetylsalicylic acid or other antiplatelet agent. Also allowed the concomitant use of quini‐ dine with dabigatran during the first two years of the study, when it was prohibited by the possibility of interaction with dabigatran.

The primary endpoint studied was the appearance of stroke or systemic embolic event and the primary safety outcome was the occurrence of serious bleeding. The criterion for noninferiority was established that the upper limit of confidence interval (CI) 97.5% of the rela‐ tive risk of occurrence of stroke or systemic embolism with dabigatran compared to warfarin was <1.46. The non-inferiority margin was established from the results of a metaanalysis with VKAs against a control treatment in patients with AF. The value of 1.46 repre‐ sents half of the 95% CI relative risk estimated effect on warfarin control. All analyzes were by intention to treat (ITT).

The results for the primary endpoint were: onset of stroke or systemic embolism in 182 pa‐ tients in the group treated with dabigatran 110 mg (1.53% per year), in 134 patients with da‐ bigatran 150 mg (1.11% per year) and 199 patients with warfarin (1.69% per year). The two treatment groups dabigatran meet the criteria for non-inferiority to be the upper limit of 95% relative risk less than 1.46 (1.11 in the first case and 0.82 in the second), but only dabiga‐ tran 150 mg was associated with lower rate of stroke and embolic events than warfarin (RR = 0.66, 95% CI 0.53 to 0.82), dabigatran 110 mg was similar to warfarin.

Regarding security, in the RE-LY study, the treatment with dabigatran was associated with an "annual rate" of major bleeding (defined as bleeding associated with a decrease in hemo‐ globin of at least 2g/dL, transfusion of at least 2 units of whole blood or symptomatic bleed‐ ing in a critical organ or area (intraocular, intracranial, intraspinal or intramuscular with compartment syndrome, retroperitoneal bleeding, bleeding or intra-articular pericardial bleeding). Severe bleeding was divided in turn into intracranial hemorrhage (intracerebral or subdural) and extracranial (gastrointestinal or not gastrointestinal). The major bleeds were categorized as critical if they met one or more of the following criteria: fatal bleeding, symptomatic intracranial bleeding, reduced hemoglobin of at least 5g/dL, transfusion of at least 4 units of whole blood or packed red cells, bleeding associated with hypotension re‐ quiring the use of intravenous inotropic agents, bleeding required surgery) of 2.71% for da‐ bigatran 110 mg, 3.11% for dabigatran 150 mg and 3.36% for warfarin. No significant difference in major bleeding between dabigatran 150 mg twice daily and warfarin; on the contrary, dabigatran 110 mg twice daily resulted in less major bleeding, RR 0.80 (95% CI: 0.69 to 0.93) p = 0.003. As for minor bleeding (defined as all non-major bleeding definition, previously expressed) annual rates were 13.16%, 14.84% and 16.37% for dabigatran 110 mg, dabigatran 150 mg and warfarin, respectively. In this case, the risk was significantly lower for dabigatran 110 mg [RR = 0.79 (95% CI: 0.74 to 0.84)] and dabigatran 150 mg [RR = 0.91 (95% CI: 0.85 to 0.97)] with respect to warfarin and was higher for dabigatran 150 mg versus dabigatran 110 mg [RR = 1.16 (95% CI: 1.08 to 1.24)]. Similarly, the risk of intracranial hemor‐ rhage was significantly lower for dabigatran 110 mg [RR = 0.31 (95% CI: 0.20 to 0.47)] and for dabigatran 150 mg [RR = 0.40 (95% CI: 0.27 to 0.60)] against warfarin and no significant differences between the two doses of dabigatran. However, the risk of bleeding severe gas‐ trointestinal was significantly higher in the group treated with dabigatran 150 mg versus warfarin [RR = 1.50 (95% CI: 1.19 to 1.89)] and versus dabigatran 110 mg [RR = 1.36 (95% CI: 1.09 to 1.70)]. The overall mortality (4%) showed no significant differences (p=0.051) be‐ tween dabigatan 150 mg twice daily and warfarin, although the rate of deaths from vascular causes was significantly lower in the group treated with dabigatran 150 mg twice daily (p=0.04).

**7.1. Dabigatran**

216 Atrial Fibrillation - Mechanisms and Treatment

<30mL/min, active liver disease and pregnancy.

possibility of interaction with dabigatran.

by intention to treat (ITT).

The RE-LY is the largest study of AF (Randomized Evaluation of Long term anticoagu‐ lant therapy) [29]. The primary endpoint was to establish non-inferiority of dabigatran etexilate compared with warfarin for a minimum of 1 year follow-up to a maximum 3 years, median follow-up of 2 years in 18.113 patients with nonvalvular AF (mean age 71 years) with at least one of the following risk factors for stroke: previous stroke or transi‐ ent ischemic attack, left ventricular ejection fraction <40%, symptoms of heart failure class 2 or higher NYHA, age >75 years or 65-74 years associated with diabetes mellitus, hypertension or coronary artery disease. Meanwhile, we excluded patients with: severe valvular disease, recent stroke, (a condition that increases the risk of bleeding), CrCl

Patients were randomized into three treatment arms: 110 mg dabigatran twice daily, dabiga‐ tran 150 mg twice daily and adjusted dose warfarin (INR 2.0-3.0). In patients randomized to receive warfarin, the average percentage of time within therapeutic range (INR = 2.0-3.0) were 64.4%. Dabigatran was administered in a blinded fashion in both treatment arms; the administration of warfarin was opened. In all branches were allowed concomitant use of acetylsalicylic acid or other antiplatelet agent. Also allowed the concomitant use of quini‐ dine with dabigatran during the first two years of the study, when it was prohibited by the

The primary endpoint studied was the appearance of stroke or systemic embolic event and the primary safety outcome was the occurrence of serious bleeding. The criterion for noninferiority was established that the upper limit of confidence interval (CI) 97.5% of the rela‐ tive risk of occurrence of stroke or systemic embolism with dabigatran compared to warfarin was <1.46. The non-inferiority margin was established from the results of a metaanalysis with VKAs against a control treatment in patients with AF. The value of 1.46 repre‐ sents half of the 95% CI relative risk estimated effect on warfarin control. All analyzes were

The results for the primary endpoint were: onset of stroke or systemic embolism in 182 pa‐ tients in the group treated with dabigatran 110 mg (1.53% per year), in 134 patients with da‐ bigatran 150 mg (1.11% per year) and 199 patients with warfarin (1.69% per year). The two treatment groups dabigatran meet the criteria for non-inferiority to be the upper limit of 95% relative risk less than 1.46 (1.11 in the first case and 0.82 in the second), but only dabiga‐ tran 150 mg was associated with lower rate of stroke and embolic events than warfarin (RR

Regarding security, in the RE-LY study, the treatment with dabigatran was associated with an "annual rate" of major bleeding (defined as bleeding associated with a decrease in hemo‐ globin of at least 2g/dL, transfusion of at least 2 units of whole blood or symptomatic bleed‐ ing in a critical organ or area (intraocular, intracranial, intraspinal or intramuscular with compartment syndrome, retroperitoneal bleeding, bleeding or intra-articular pericardial bleeding). Severe bleeding was divided in turn into intracranial hemorrhage (intracerebral or subdural) and extracranial (gastrointestinal or not gastrointestinal). The major bleeds

= 0.66, 95% CI 0.53 to 0.82), dabigatran 110 mg was similar to warfarin.

The results of dabigatran 150 mg dose showed that the benefit is somewhat larger than war‐ farin in CHADS2≥ 2 while the hemorrhagic risk is similar in both groups. In CHADS2 = 0-1 the benefit is also somewhat higher than warfarin while the hemorrhagic risk is somewhat lower. A dose of 110 mg the benefit and bleeding risk is similar in every category of CHADS2 except for the category CHADS2 = 0-1 where the risk is somewhat lower.

Dropout rates were higher with dabigatran: 14.5% with dabigatran 110 mg, 15.5% with 150 mg dabigatran and 10.2% with warfarin the first year and 20.7% with dabigatran 110 mg, 21.2% with dabigatran 150 mg and 16.6% with warfarin the second year. There were more withdrawals due to serious adverse events with dabigatran (2.7%) than with war‐ farin (1.7%).

The incidence of myocardial infarction was higher with dabigatran 110 mg twice daily (0.72%, p = 0.07) and dabigatran 150 mg twice daily (0.74%, p = 0.048) than warfarin (0.53%), having calculated that myocardial infarction could occur for every 500 patients treated with dabigatran. With the correction of the results of RE-LY study the differentiation in the appa‐ rition of the myocardial infarction no longer statistically significant. However, a meta-analy‐ sis of 7 trials published recently concluded that the use of dabigatran is associated with an increased risk of myocardial infarction or acute coronary syndrome in a broad spectrum of patients compared with VKAs, antiplatelet or placebo [30]. Although the absolute risk may be low, it is necessary to closely monitor patients and the importance of improving pharma‐ covigilance systems [31]*.*

#### **7.2. Rivaroxaban**

The ROCKET AF study (Rivaroxaban Once daily, oral, direct factor Xa inhibition Com‐ pared with vitamin K for prevention of stroke Antagonism and Embolism Trial in Atrial fibrillation) compared the clinical outcomes of rivaroxaban at doses of 20 mg/day (15 mg/day for those with estimated CrCl 30-49 mL/min ) with warfarin dose-adjusted INR in patients with AF. It is a prospective, randomized, double-blind, parallel group, multi‐ center, event-based and non-inferiority which involved 14.264 patients. The patients had high risgo of stroke (CHADS2 score >2 in 90%) [32, 33]. It was shown that the new anti‐ coagulant was non-inferior to warfarin in the combined primary endpoint, which includ‐ ed stroke and systemic embolism. Embolic events were presented to the central nervous system or systemic 1.7% per year in the rivaroxaban group compared with 2.2% in the warfarin group, which has met the criterion for non-inferiority. However, ITT analysis showed that superiority failed. The incidence rates of primary safety outcome (major bleeding episodes and no clinically relevant non-major bleeding) were similar in both treatment groups but, with rivaroxaban, there was a significant reduction in fatal bleed‐ ing, as well as an increase in gastrointestinal bleeds and bleeds requiring transfusion. Premature discontinuation of treatment was more common with rivaroxaban (23.9%) than with warfarin (22.4%). The duration of follow-up was 12-32 months.

2.0-3.0). The study was designed to demonstrate non-inferiority of apixaban compared to warfarin. Analysis is performed of non-inferiority trial and after an analysis of superiority. The primary efficacy endpoint was the composite of stroke and systemic embolism. The pri‐ mary safety outcome was major bleeding. The mean duration of follow-up was 1.8 years. The study included 18.201 patients with AF at high risk of systemic and cerebral embolism. Cerebrovascular events were 1.27% per year in the apixaban group versus 1.60% in the war‐ farin group (p <0.001 for non-inferiority and p = 0.01 for superiority), bleeding of 2.13% ver‐ sus 3.09% for year (p <0.001), respectively. Significantly decreased the incidence of any type of bleeding, major bleeding and intracranial bleeding and not change the frequency of ap‐ pearance of gastrointestinal bleeding. Mortality from all causes was 3.52% versus 3.94%, demonstrating the superiority of apixaban compared to warfarin in preventing stroke or central nervous system systemic fewer bleeding complications and lower mortality. Cere‐ brovascular events in patients with CHADS2 ≥3 were 1.9% per year in patients treated with apixaban compared to 2.8% per year in patients treated with warfarin; CHADS2 = 0-1, 0.7% per year versus 0.9% per year and CHADS2 = 2, 1.2% per year versus 1.4% per year. In pa‐ tients under 65 years no difference in efficacy between both groups, but in patients over 65

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In conclusion, treatment with apixaban compared to warfarin in AF patients with more than one risk factor reduces the incidence of stroke and systemic embolism by 21% (p = 0.01), re‐ duced major bleeding by 31% (p <0.001) and reduces mortality by 11% (p = 0.047) [35].

Taking into account the results of the studies so far mentioned, there are some differences in patients enrolled in the RE-LY, the ROCKET AF, the AVERROES and the ARISTOTLE. The study population ARISTOTLE included subjects both with a CHADS2 score of 1 point and those of scores. In the RE-LY incorporated population according to the CHADS2 score was mild-moderate risk (32% of patients with a CHADS2 of 3 to 6 points) and the ROCKET-AF population included was moderate to severe (87% patients had a CHADS2 risk score (of 3 to 6 points) which makes comparisons difficult between these studies. RE-LY and ARISTOTLE have similar characteristics on patient demographics (age, gender...) and in the risk of stroke (average CHADS2 score of 2.1). However, ROCKET AF patients were slightly older (median age 73 years), were at high risk of stroke (mean CHADS2 score of 3.5), and 55% were a sec‐ ondary prevention population [36]. Exclusion criteria of patients pose leave out AF patients eligible for treatment with VKAs, as those who have suffered a recent stroke or those with

They are non-inferiority studies. The European Medicines Agency (EMEA) recommended in these studies an ITT and per protocol analysis (PP). In the RE-LY is not a PP (which could favor dabigatran) and also the non-inferiority margin has questionable clinical relevance. The superiority analysis showed more effectively to the highest dose of dabigatran. The ROCKET AF results PP were slightly significant in favor of rivaroxaban while ITT results demonstrate the non-inferiority of rivaroxaban with warfarin. ARISTOTLE and AVERROES studies also reflect the non-inferiority of apixaban versus warfarin however, the results were

years the difference is 0.9%.

**7.4. Methodological limitations of studies**

liver enzyme elevations 2 times the upper limit of normal.

#### **7.3. Apixaban**

The AVERROES study is a multicenter, randomized, double-blind and double-dummy (Apixaban Versus Stroke Acetylsalicylic Acid to Prevent Stroke in Atrial Fibrillation Patients Who Have Failed or Are Unsuitable for Vitamin K Antagonist Treatment) comparing apixa‐ ban 5 mg twice daily (2.5 mg twice daily in patients ≥80 years, weight ≤60 kg or with a se‐ rum creatinine ≥1.5 mg/dL) versus acetylsalicylic acid 81-324 mg daily in 5.599 patients with AF at high risk of stroke and without indication for treatment with VKAs or by difficulties in anticoagulation or because the patient refused anticoagulation therapy.

The trial was stopped early, after about a year after intermediate analysis showed a signifi‐ cant reduction of 50% in the risk of stroke. There were 1.6% of cerebral and systemic embolic events in the apixaban group compared to 3.5% in the acetylsalicylic acid group. The fre‐ quency of bleeding was similar (1.4 versus 1.2% per year); there was no difference between patients treated with apixaban and acetylsalicylic acid on the incidence of major bleeding, intracranial hemorrhage, or gastrointestinal bleeding even if appreciate a significant increase of the total number of bleeding (major and minor). Mortality was lower in the apixaban group (3.5% per year) than acetylsalicylic acid (4.4% per year), results that corroborate the greatest benefit of anticoagulant therapy in AF. In patients with AF for whom therapy is in‐ adequate VKAs, apixaban reduces the risk of stroke or systemic embolism without increas‐ ing the risk of major bleeding or intracranial hemorrhage [34].

The ARISTOTLE study is a multicenter, randomized, double-blind and double-dummy (Apixaban for Reduction in Stroke and Other Events in Atrial Fibrillation thromboembolic) comparing apixaban 5 mg orally twice daily (2.5 mg twice daily in patients ≥80 years, weight ≤60 kg or with a serum creatinine ≥1.5 mg/dL) versus adjusted-dose warfarin (INR 2.0-3.0). The study was designed to demonstrate non-inferiority of apixaban compared to warfarin. Analysis is performed of non-inferiority trial and after an analysis of superiority. The primary efficacy endpoint was the composite of stroke and systemic embolism. The pri‐ mary safety outcome was major bleeding. The mean duration of follow-up was 1.8 years. The study included 18.201 patients with AF at high risk of systemic and cerebral embolism. Cerebrovascular events were 1.27% per year in the apixaban group versus 1.60% in the war‐ farin group (p <0.001 for non-inferiority and p = 0.01 for superiority), bleeding of 2.13% ver‐ sus 3.09% for year (p <0.001), respectively. Significantly decreased the incidence of any type of bleeding, major bleeding and intracranial bleeding and not change the frequency of ap‐ pearance of gastrointestinal bleeding. Mortality from all causes was 3.52% versus 3.94%, demonstrating the superiority of apixaban compared to warfarin in preventing stroke or central nervous system systemic fewer bleeding complications and lower mortality. Cere‐ brovascular events in patients with CHADS2 ≥3 were 1.9% per year in patients treated with apixaban compared to 2.8% per year in patients treated with warfarin; CHADS2 = 0-1, 0.7% per year versus 0.9% per year and CHADS2 = 2, 1.2% per year versus 1.4% per year. In pa‐ tients under 65 years no difference in efficacy between both groups, but in patients over 65 years the difference is 0.9%.

In conclusion, treatment with apixaban compared to warfarin in AF patients with more than one risk factor reduces the incidence of stroke and systemic embolism by 21% (p = 0.01), re‐ duced major bleeding by 31% (p <0.001) and reduces mortality by 11% (p = 0.047) [35].

#### **7.4. Methodological limitations of studies**

**7.2. Rivaroxaban**

218 Atrial Fibrillation - Mechanisms and Treatment

**7.3. Apixaban**

The ROCKET AF study (Rivaroxaban Once daily, oral, direct factor Xa inhibition Com‐ pared with vitamin K for prevention of stroke Antagonism and Embolism Trial in Atrial fibrillation) compared the clinical outcomes of rivaroxaban at doses of 20 mg/day (15 mg/day for those with estimated CrCl 30-49 mL/min ) with warfarin dose-adjusted INR in patients with AF. It is a prospective, randomized, double-blind, parallel group, multi‐ center, event-based and non-inferiority which involved 14.264 patients. The patients had high risgo of stroke (CHADS2 score >2 in 90%) [32, 33]. It was shown that the new anti‐ coagulant was non-inferior to warfarin in the combined primary endpoint, which includ‐ ed stroke and systemic embolism. Embolic events were presented to the central nervous system or systemic 1.7% per year in the rivaroxaban group compared with 2.2% in the warfarin group, which has met the criterion for non-inferiority. However, ITT analysis showed that superiority failed. The incidence rates of primary safety outcome (major bleeding episodes and no clinically relevant non-major bleeding) were similar in both treatment groups but, with rivaroxaban, there was a significant reduction in fatal bleed‐ ing, as well as an increase in gastrointestinal bleeds and bleeds requiring transfusion. Premature discontinuation of treatment was more common with rivaroxaban (23.9%)

than with warfarin (22.4%). The duration of follow-up was 12-32 months.

in anticoagulation or because the patient refused anticoagulation therapy.

ing the risk of major bleeding or intracranial hemorrhage [34].

The AVERROES study is a multicenter, randomized, double-blind and double-dummy (Apixaban Versus Stroke Acetylsalicylic Acid to Prevent Stroke in Atrial Fibrillation Patients Who Have Failed or Are Unsuitable for Vitamin K Antagonist Treatment) comparing apixa‐ ban 5 mg twice daily (2.5 mg twice daily in patients ≥80 years, weight ≤60 kg or with a se‐ rum creatinine ≥1.5 mg/dL) versus acetylsalicylic acid 81-324 mg daily in 5.599 patients with AF at high risk of stroke and without indication for treatment with VKAs or by difficulties

The trial was stopped early, after about a year after intermediate analysis showed a signifi‐ cant reduction of 50% in the risk of stroke. There were 1.6% of cerebral and systemic embolic events in the apixaban group compared to 3.5% in the acetylsalicylic acid group. The fre‐ quency of bleeding was similar (1.4 versus 1.2% per year); there was no difference between patients treated with apixaban and acetylsalicylic acid on the incidence of major bleeding, intracranial hemorrhage, or gastrointestinal bleeding even if appreciate a significant increase of the total number of bleeding (major and minor). Mortality was lower in the apixaban group (3.5% per year) than acetylsalicylic acid (4.4% per year), results that corroborate the greatest benefit of anticoagulant therapy in AF. In patients with AF for whom therapy is in‐ adequate VKAs, apixaban reduces the risk of stroke or systemic embolism without increas‐

The ARISTOTLE study is a multicenter, randomized, double-blind and double-dummy (Apixaban for Reduction in Stroke and Other Events in Atrial Fibrillation thromboembolic) comparing apixaban 5 mg orally twice daily (2.5 mg twice daily in patients ≥80 years, weight ≤60 kg or with a serum creatinine ≥1.5 mg/dL) versus adjusted-dose warfarin (INR Taking into account the results of the studies so far mentioned, there are some differences in patients enrolled in the RE-LY, the ROCKET AF, the AVERROES and the ARISTOTLE. The study population ARISTOTLE included subjects both with a CHADS2 score of 1 point and those of scores. In the RE-LY incorporated population according to the CHADS2 score was mild-moderate risk (32% of patients with a CHADS2 of 3 to 6 points) and the ROCKET-AF population included was moderate to severe (87% patients had a CHADS2 risk score (of 3 to 6 points) which makes comparisons difficult between these studies. RE-LY and ARISTOTLE have similar characteristics on patient demographics (age, gender...) and in the risk of stroke (average CHADS2 score of 2.1). However, ROCKET AF patients were slightly older (median age 73 years), were at high risk of stroke (mean CHADS2 score of 3.5), and 55% were a sec‐ ondary prevention population [36]. Exclusion criteria of patients pose leave out AF patients eligible for treatment with VKAs, as those who have suffered a recent stroke or those with liver enzyme elevations 2 times the upper limit of normal.

They are non-inferiority studies. The European Medicines Agency (EMEA) recommended in these studies an ITT and per protocol analysis (PP). In the RE-LY is not a PP (which could favor dabigatran) and also the non-inferiority margin has questionable clinical relevance. The superiority analysis showed more effectively to the highest dose of dabigatran. The ROCKET AF results PP were slightly significant in favor of rivaroxaban while ITT results demonstrate the non-inferiority of rivaroxaban with warfarin. ARISTOTLE and AVERROES studies also reflect the non-inferiority of apixaban versus warfarin however, the results were 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 range, implying poor control within the clinical trial.

not significantly different from dabigatran 110 mg twice daily. There were no significant dif‐ ferences between apixaban and dabigatran 110 mg twice daily. Apixaban had lower major or clinically relevant bleeding (by 34%) versus ribaroxaban. When compared with rivaroxa‐ ban, dabigatran 110 mg twice daily was associated with less mayor bleeding (by 23%) and intracranial bleeding (by 54%). No significant differences myocardial infarction events be‐ tween dabigatan (both doses) and apixaban. However, only a head-to-head direct compari‐ son of the different NOACs would be able to answer the question of efficacy/safety

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An advantage of the NACOs proposes absence monitoring. Instead, experts recommend that in chronic treatment with narrow therapeutic window and potentially serious complica‐ tions (stroke/hemorrhage), lack of control is much more harmful than adequate control. The regular monitoring to adjust and correct the treatment regimen and distinguish, if complica‐

Are emerging post-marketing data on major bleeding and death with dabigatran: Japan (5 deaths and 81 cases of severe reactions), Australia (7 deaths and 24 serious reactions) and Europe (21 deaths). In the subsequent reanalysis of data from the RE-LY was a higher inci‐ dence of stroke, myocardial infarction and major bleeding compared to those initially re‐

No specific antidote proved effective, which hinder the resolution of bleeding emergencies. In addition, the high cost compared to VKAs is a major limitation. Have been published some cost-effectiveness data for dabigatran, and dabigatran appears to be cost-effective for

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

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

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

differences between them in the prevention of stroke in AF.

ported, in those over 75 years more extracranial bleeding [38].

most patients, except in those with very well-controlled INRs [39,40].

data long-term selected populations and are generating security alerts.

tions, treatment failure or lack of adherence.

**8. Current recommendations - Caution**

interactions and food.

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% of ARISTOTLE).

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‐ tients who would benefit from low dose.

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 not significantly different from dabigatran 110 mg twice daily. There were no significant dif‐ ferences between apixaban and dabigatran 110 mg twice daily. Apixaban had lower major or clinically relevant bleeding (by 34%) versus ribaroxaban. When compared with rivaroxa‐ ban, dabigatran 110 mg twice daily was associated with less mayor bleeding (by 23%) and intracranial bleeding (by 54%). No significant differences myocardial infarction events be‐ tween dabigatan (both doses) and apixaban. However, only a head-to-head direct compari‐ son of the different NOACs would be able to answer the question of efficacy/safety differences between them in the prevention of stroke in AF.

An advantage of the NACOs proposes absence monitoring. Instead, experts recommend that in chronic treatment with narrow therapeutic window and potentially serious complica‐ tions (stroke/hemorrhage), lack of control is much more harmful than adequate control. The regular monitoring to adjust and correct the treatment regimen and distinguish, if complica‐ tions, treatment failure or lack of adherence.

Are emerging post-marketing data on major bleeding and death with dabigatran: Japan (5 deaths and 81 cases of severe reactions), Australia (7 deaths and 24 serious reactions) and Europe (21 deaths). In the subsequent reanalysis of data from the RE-LY was a higher inci‐ dence of stroke, myocardial infarction and major bleeding compared to those initially re‐ ported, in those over 75 years more extracranial bleeding [38].

No specific antidote proved effective, which hinder the resolution of bleeding emergencies. In addition, the high cost compared to VKAs is a major limitation. Have been published some cost-effectiveness data for dabigatran, and dabigatran appears to be cost-effective for most patients, except in those with very well-controlled INRs [39,40].
