Management of AF have been addressed essentially in lowering thrombo-embolic stroke by anticoagulants and/or by antiplatelet drugs. Thus, a risk score has been validated to identify patients’ categories, which could better benefit from antiplatelet or anticoagulant treatment. The CHADS2 score,37 which includes Congestive heart failure, Hypertension, Age, Diabetes and previous Stroke, was firstly introduced to identify patients to be treated or not with an antithrombotic treatment (aspirin or oral anticoagulant). In the attempt of better discriminating patients at low or high risk of stroke the new CHA2DS2-VASc score38 was recently introduced. This new score, which is characterized for the inclusion of two age cut-off,38 female gender and vascular disease as independent risk factors for stroke, divides AF patients in two categories: patients at low risk (score 0-1), and patients at high risk (score ≥2) of future cerebrovascular events. This classification has important implications for clinical management and treatment of patients.39 In fact, while AF patients with CHA2DS2-VASc score of 0 are not candidates to receive any anti-thrombotic prophylaxis (truly low-risk patients), those with CHA2DS2-VASc score of 1 could be treated with an oral anticoagulant or, alternatively, with aspirin but a clear definition of this approach is still lacking.39 Finally, all AF patients with CHA2DS2-VASc score ≥2 should receive an anticoagulant therapy with oral vitamin K antagonists (VKAs) or with the new oral anticoagulants (NOACs), in the absence of contraindications to these treatments.
Globally considered, trials with anticoagulants clearly demonstrated a net clinical benefit, which in fact was documented by a 68% risk reduction compared to untreated patients.40 Concerns related to bleeding complication, particularly in the brain, blood monitoring and underuse of VKAs41 lead to develop NOACs which include dabigatran etexilate, a direct thrombin inhibitor, and inhibitors of factor Xa, such as rivaroxaban, apixaban, and edoxaban42.
The use of NOACs presents some considerable benefits, consisting in fewer drug interactions than warfarin, and having a predictable anticoagulant effect, thereby apparently not requiring a continuous monitoring of laboratory values. A recent meta-analysis by Ruff43 examined the four phase III trials that compared, for non-inferiority, warfarin versus dabigatran, rivaroxaban, apixaban and edoxaban respectively. The meta-analysis included 42411 participants receiving a NOAC and 29272 subjects on warfarin treatment. NOACs significantly reduced stroke or systemic embolic events, haemorrhagic stroke and intracranial haemorrhage and all-cause mortality but increased gastrointestinal bleeding. The benefit of NOACs compared with warfarin in reducing stroke or systemic embolic events was consistent across all subgroups examined.
Although these new drugs significantly enlarge the medical toolbox, NOACs are not currently suitable for all AF patients and some caveat must be taken into account before prescribing them.
Table 2. Open issues
|-Treatment of elderly AF patients with novel oral anticoagulants is still to be more properly addressed|
|-Therapeutic strategies to reduce the risk of myocardial infarction in atrial fibrillation patients must be planned |
|-Knowledge of blood concentration of novel oral anticoagulants is mandatory|
|-Large randomized prospective clinical trials are needed to investigate the effect of combining oral anticoagulants with statins for cardiovascular event prevention|
An important relevant point concerns the differences between patients with a good time in therapeutic range (TTR) defined as a TTR>66% and those below. The pooled analysis of the trials performed by a recent meta-analysis41 demonstrated that the favourable effect of NOACs in the reduction of bleeding events is evident only in patients with a low quality anticoagulation (TTR<66%).41 As a result, NOACs should not be the first choice of treatment for patients with good anticoagulation control with VKAs.
Even if globally considered NOACs reduce cardiovascular events, a sub analysis showed that low-dose NOAC regimens are able to reduce the incidence of haemorrhagic stroke, but are not as effective as warfarin to prevent ischemic stroke and myocardial infarction. Another point that needs to be taken into consideration concerns the use of NOACs in patients with renal failure. Patients with severe renal failure (eGFR <30 ml/min) and/or on dialysis treatment were not included in clinical trials, so VKAs are still the recommended treatment for these patients.
Apart from these specific issues, there is also another relevant point, which must be taken into account. The real advantage of NOACs compared to warfarin would consist on unnecessary monitoring of drug concentration in the blood. From patients with eGFR between 30-50 ml/min recent analysis from the RE-LY trial,44 outlined the wide variation in term of dabigatran concentration in blood with an increase of 47% compared to those with eGFR >80 ml/min. Of particular relevance was the fact that in patients with 30-50 ml/min dabigatran concentration could vary from as low as 28 ng/ml from as high as 215 ng/ml depending on the dosage used; age >75 years and female gender could be associated with 68% and 30% increase of dabigatran concentration respectively. Such variations were of particularly relevance for safety and clinical outcomes as low or high dabigatran concentration were associated with an enhanced risk of stroke or bleeding respectively. Analysis of dabigatran concentration, which was putatively associated with lower risk of stroke and bleeding , suggested that values around 100 ng/ml would be theoretically optimal, with an increased risk of stroke and bleeding for values <40ng/ml and >200ng/ml respectively. Based on this, predicting the risk of stroke and bleeding in old patients and females is almost difficult without precise information on drug blood levels. According to recent literature data, such wide variation of dabigatran levels is likely to account for the increased risk of bleeding and death which has been observed particularly in elderly patients.45,46 Thus, in a recent survey from nationwide study the shift from VKSs to dabigatran was associated with a surprisingly enhanced risk for both thrombo-embolism and bleeding disorders clearly indicating the need for an accurate follow-up of AF patients on NOACs.47 This finding questions the assumption that dabigatran can be used at fixed doses and raises concern on the claim that this drug category does not need blood monitoring. Unfortunately, data regarding the other NOACs are not yet available; thereby it remains to be clarified if the wide blood variability of NOACs is limited to dabigatran or can be observed with the other new anticoagulants.
A recent work by Soliman and colleagues48 analysed the incidence of MI in a population-cohort study including 1631 participants with AF. During a median follow-up of 4.5 years, the incidence rate of MI was 1.2 per 100 person-years, which was significantly higher compared to patients without AF also after adjustment for traditional atherosclerotic risk factors; this finding suggested, therefore, that AF per se is an independent predictor of MI. The incidence rate of MI reported by Soliman et al. is apparently higher compared to that recently shown by the interventional trial with the NOACs. Thus, globally considered, the rate of MI was in average 0.8% per year, with a range from 0.5 to 4%/year.5 Even if such difference may perhaps be explained by the fact that <50% of AF patients on the Soliman’ study were on treatment with warfarin, other reports indicated, however, that in the real word of AF patients on treatment with warfarin the annual incidence rate of MI is actually elevated (> 1% year), and even more frequent than stroke.49 This difference with the interventional trials may depend on the fact that patients in the real world are older and at higher risk of athero-thrombosis despite adequate anticoagulation. At this regard, a previous study demonstrated that a good anticoagulation is associated with a lower risk of MI in AF50 but the interplay between TTR and MI rate in AF population has not been clarified. The relationship between MI and AF is even more complicated when the NOACs are taken into account. Thus, no differences in MI rate were observed between NOACs and warfarin when all NOACs dosages were considered; conversely, compared to warfarin, a significant increase of MI rate was detected in AF patients with low NOACs doses. Even if such apparent paradox has not been explained, treatment of AF patients with or at risk of MI with low doses of NOACs should be carefully considered.
Management of AF patients at risk or with previous MI is, therefore, becoming a novel hot topic which needs to be addressed soon, as preventing MI in AF would reduce the risk related of combining oral anticoagulants with aspirin. Such association is quite frequent in AF as shown by interventional trails with NOACs in which 29-41% of patients included were treated with such combination despite no evidence of a clear benefit and serious risks of bleeding.51,52 So far, however, no strategy has been planned to reduce the risk of myocardial infarction in AF and its sequelae, nor it has been clarified if there are AF patients without previous coronary events who are at higher risk of myocardial infarction. In this context statins may be an attractive option as they have been able to reduce the risk of myocardial infarction in primary and secondary prevention trials.53 Furthermore, statins possess antithrombotic properties which may return useful in this setting, which is associated with a systemic and local on-going pro-thrombotic state.54 Statins have been described to be useful to reduce new onset AF,55,56 the recurrences of AF after electrical cardio-version/ablation,57,58 after cardiac surgery59 or in patients presenting with acute coronary syndrome.60 Nevertheless, the effect of statin use in reducing vascular events in AF patients has never been investigated in prospective randomized trials.