Although the antithrombotic effect of conventional oral anticoagulant warfarin is clear and reliable, its metabolism is easily affected by food and drugs, and the time to drug onset and expiration is long; individual therapeutic response to warfarin is related to genetic background; the therapeutic window of warfarin is narrow, and frequent monitoring of patient’s coagulation function is required to titrate the dose to maximize the balance between anticoagulation effect and bleeding risk, which leads to poor compliance of patients with the drug. In contrast, new oral anticoagulants (NOACs) have outstanding advantages such as stable pharmacokinetics, fixed doses, no frequent monitoring of coagulation, few interactions with drugs and food, and good drug safety. In this paper, we intend to review the results of clinical trials on NOACs and interpret the updated guidelines on anticoagulation and antithrombotic therapy to provide reference for the standardized clinical use of NOACs.
Since their introduction in the 1950s, vitamin K antagonists, represented by warfarin, have been the only and irreplaceable oral anticoagulants widely used to prevent thromboembolic events in patients with thrombophilia and atrial fibrillation (AF). Although the antithrombotic effect of warfarin is clear and reliable, there are still many problems with the drug itself and its use: the metabolism of warfarin is easily affected by food and drugs, and the drug takes a long time to start and expire; the individual response to warfarin treatment is related to the genetic background; the narrow window of warfarin treatment requires frequent monitoring of the patient’s coagulation to titrate the dose in order to maximize the balance between the anticoagulant effect and the risk of bleeding. This leads to poor patient compliance with the drug. Over the years, efforts have been made to develop new antithrombotic drugs that are safer, more effective, and more convenient, and new anticoagulants such as direct thrombin inhibitors (dabigatran) and direct factor Xa inhibitors (rivaroxaban, apixaban, and edoxaban) have recently been introduced. In this paper, we intend to review the clinical trial results of new oral anticoagulants (NOACs), interpret the updated guidelines for anticoagulation and antithrombotic therapy, and provide reference for the standardized clinical use of these drugs.
1 Pharmacokinetic characteristics of new oral anticoagulants
Compared with warfarin, the pharmacokinetic characteristics of NOACs are more stable (Table 1), less influenced by drugs and food, and faster onset of action and expiration.
Table 1 Comparison of the pharmacokinetics of warfarin and new oral anticoagulants
Note: CYP: cytochrome
2 Application of new oral anticoagulants in non-valvular atrial fibrillation
Atrial fibrillation is the most common clinical arrhythmia, and anticoagulation is one of the core strategies in the treatment of AF; therefore, patients with AF are the mainstay of the use of NOACs. To date, several large prospective randomized controlled trials have confirmed the efficacy and safety of NOACs in preventing stroke or embolic events in patients with non-valvular AF. 2009, RE-LY trial: enrolled 18,113 patients with a median follow-up of 2 years, showed that dabigatranate anticoagulation was no worse than, or even better than, warfarin in terms of efficacy and had fewer total bleeding complications than warfarin. 2010. ROCKET-AF trial: enrolled 14,264 patients with a median follow-up of 707 days, the results confirmed that rivaroxaban was as effective as warfarin in preventing stroke and did not increase the risk of bleeding in patients. 2011, ARISTOTLE trial: enrolled 18,201 patients with a median follow-up of 1.8 years, the results showed that apixaban was more effective and safer than warfarin in preventing stroke in patients with non-valvular atrial fibrillation. In 2011, the AVERROES trial enrolled 5,599 patients with a mean follow-up of 1.1 years to compare the efficacy and safety of apixaban with that of aspirin for stroke prevention in patients with atrial fibrillation who were intolerant or had contraindications to warfarin, and was terminated early because the mid-term follow-up analysis showed that apixaban was significantly more effective than aspirin.
These evidence-based findings suggest that NOACs are at least as effective as warfarin in preventing stroke or embolic events in patients with non-valvular atrial fibrillation, but with a higher safety profile. The RELY-ABLE trial, recently published in Circulation, looked at patients who continued to take dabigatranide after the RE-LY trial (5,851 patients with a median follow-up of 2.3 years) and showed that the risk of ischemic stroke and major bleeding events in patients who continued to take dabigatranide was similar to the results of the RE-LY trial. For the first time, the efficacy and safety of long-term dabigatranate use was confirmed. In addition, large, longer follow-up registry studies, GLORIA and GARFIELD, are ongoing, and we expect these studies to provide “real world” information on the use of NOACs for the prevention of thromboembolic events in non-valvular atrial fibrillation.
Based on the evidence from these trials, the status of NOACs in AF treatment guidelines has been increasing in recent years. 2010 European Society of Cardiology (ESC) AF treatment guidelines first cited the RE-LY and AVERROES studies that were published at that time, but did not specifically recommend NOACs for anticoagulation in atrial fibrillation. With the publication of the results of the ROCKET-AF and other trials, the 2011 update of the American College of Cardiology (ACC)/American Heart Association (AHA)/Heart Rhythm Society (HRS) guidelines for the treatment of atrial fibrillation first recommended that patients with atrial fibrillation who have risk factors for stroke or systemic embolism, who do not have an implanted prosthetic heart valve or hemodynamically compromised valve disease, and who do not have severe renal insufficiency [creatinine clearance (CrCl) <15 ml/min] or severe liver disease (coagulation affecting baseline status), dabigatran may be used as an alternative therapy to warfarin for stroke and systemic embolism prevention (recommendation level I, evidence level B). Subsequently, the ESC 2012 guideline update for the treatment of atrial fibrillation recommended that patients with non-valvular atrial fibrillation who have an indication for anticoagulation and who are inappropriate or unwilling to be anticoagulated with warfarin and have no contraindications to NOACs may be directly anticoagulated with any of the NOACs (recommendation level I, level of evidence B); even NOACs may be the preferred oral anticoagulant (recommendation level IIa, level of evidence B) .
2.1 Anticoagulation in Atrial Fibrillation Combined with Chronic Kidney Disease
The guidelines state that the benefit-risk ratio of NOACs in patients with mild-to-moderate chronic renal insufficiency (CrCl: 30-80 ml/min) is similar to that of warfarin application, and even the risk of bleeding is lower; it is safe and reasonable to apply NOACs to this group of patients, but renal function monitoring should be enhanced. Given that more than 80% of dabigatran is cleared by the kidneys, the dose of dabigatran should be reduced and the frequency of renal function monitoring should be increased in patients with severe renal insufficiency, and the doses of rivaroxaban and apixaban should be reduced accordingly. Due to the lack of evidence-based medical evidence, the guidelines do not recommend NOACs for patients with atrial fibrillation with advanced chronic kidney disease or requiring dialysis (CrCl<15 ml/min). Table 2 shows the recommendations of the 2013 European Heart Arrhythmia Association (EHRA) clinical practice guidelines for dose adjustment of NOACs at different CrCl.
Table 2 Recommendations for dose adjustment of corresponding NOACs at different CrCl in the 2013 EHRA practice guidelines
Note: CrCl: creatinine clearance EHRA: European Heart Arrhythmia Association NOACs: new oral anticoagulants
2.2 Anticoagulation in atrial fibrillation combined with coronary artery disease
The 2013 EHRA clinical practice guideline for NOACs recommends that the following three conditions should be treated differently.
(1) acute coronary syndrome (ACS) in patients with atrial fibrillation: stop NOACs in the acute phase, switch to aspirin plus P2Y12 inhibitors (mainly clopidogrel) for dual antiplatelet therapy (DAPT), and add heparin anticoagulation when NOACs are exhausted, preferably choosing plain heparin or bivalirudin rather than low-molecular heparin; for patients at high risk of bleeding, stop NOACs and then take For patients with high risk of bleeding, aspirin can be taken first after stopping NOACs, and then P2Y12 inhibitors can be added after NOACs have worn off. If patients need interventional therapy, it is better to wait until the effect of NOACs wears off; if urgent surgery is needed, anticoagulation and antiplatelet drugs should be selected according to the results of patients’ coagulation indexes, but this strategy lacks evidence-based medical evidence and remains controversial, so it is not routinely recommended; in percutaneous coronary intervention (PCI), anticoagulation is better to choose common heparin or bivalirudin rather than low-molecular heparin, and as long as it can be safely stopped after the procedure A step-down antithrombotic regimen for patients with ACS with atrial fibrillation is similar to the traditional warfarin combination antithrombotic strategy from stabilization to one year after PCI, provided that heparin can be safely discontinued after the procedure and that low-dose NOACs can be restarted without discontinuing DAPT. In patients with advanced age or renal insufficiency, the guidelines still recommend the traditional warfarin combination antithrombotic strategy due to the lack of evidence-based medical evidence for NOACs.
②Recent (<1 year) occurrence of new-onset atrial fibrillation in patients with acs: in principle, triple antithrombotic therapy should be avoided < strong="">as much as possible. The risk of coronary events and stroke events in atrial fibrillation should be weighed: if the former risk is low and the latter high, especially if accompanied by a high risk of bleeding, warfarin alone (after 1 month of DAPT for bare metal stents and after 3 to 6 months of DAPT for drug stents) may be given, but there is no evidence whether NOACs alone can be combined with coronary antithrombotic therapy; conversely, if the former risk is high and the latter low, then the DAPT regimen of antithrombotic therapy may be continued. If both risks are high, an oral anticoagulant (warfarin or NOACs) plus an antiplatelet agent (clopidogrel is preferred) may be used.
(iii) Stable coronary artery disease combined with atrial fibrillation (ACS > 1 year, or after elective placement of bare metal stents > 1 month, drug-eluting stents > 6 months): the guidelines state that although there are no clinical studies specifically for similar conditions, experience suggests that NOACs alone may be more effective than warfarin; low-dose aspirin may be added for patients at low risk of bleeding and high risk of coronary events, but patients must be clearly informed that The risk of hemorrhage may be increased as a result.
2.3 Anticoagulation in patients with atrial fibrillation in the perioperative/peri-catheter ablation period
In patients with atrial fibrillation taking NOACs who are undergoing surgical procedures, the decision to discontinue NOACs should be made by the risk of bleeding during the procedure itself: for procedures with no clinically significant risk of bleeding (e.g., tooth extraction and glaucoma surgery) or a small risk of bleeding, discontinuation of NOACs for 18 to 24 hours before surgery is sufficient; for procedures with a risk of major bleeding, discontinuation should be at least 48 hours. For emergency surgery, delay the procedure until at least 12 hours after the last dose if possible, preferably 24 hours after the dose. Except for a few procedures where complete hemostasis is possible, anticoagulation with NOACs should be restarted at least 48 to 72 hours after the procedure, during which time heparin can be started at 6 to 8 hours after the procedure if necessary and in the absence of active bleeding. The guidelines do not provide very specific recommendations regarding the use of NOACs in the perioperative period for catheter ablation of atrial fibrillation, as only a few observational trials and case-control studies of dabigatranate have been performed to date, except to cautiously note that a perioperative heparin transition and restart of NOACs anticoagulation at the appropriate time is feasible; however, it is also noted that, compared with an uninterrupted warfarin strategy in the perioperative period, discontinuing NOACs for too short a time and/or without heparin transition can both lead to an increased risk of bleeding/thrombosis.
3 Anticoagulation with Novel Oral Anticoagulants in Patients After Mechanical Valve Replacement
In 2012, the U.S. Food and Drug Administration (FDA) issued a statement prohibiting the use of dabigatranate for anticoagulation in patients with mechanical valves based on the phase II trial RE-ALIGN study (ClinicalTrials.gov. registry number: NCT01505881), which was forced to be terminated early. The study found that mechanical valve-related complications, including stroke, myocardial infarction, and valve thrombosis, occurred more frequently in patients taking dabigatranate compared with those taking warfarin. To date, no studies support the use of NOACs for anticoagulation in patients after mechanical valve replacement.
4 Novel Oral Anticoagulants in Venous Thromboembolism Prevention and Treatment
In recent years, numerous clinical trials have evaluated the antithrombotic role of NOACs in the prevention of venous thromboembolic (VTE) events (Table 3). Based on these studies, the European Medicines Agency (EMA) approved rivaroxaban, apixaban, and dabigatran for the prevention and treatment of VTE; however, the FDA approved only the first two drugs. In addition, the 9th edition of the American College of Chest Physicians Antithrombotic Guidelines (ACCP-9) also recommends NOACs in VTE: dabigatran, apixaban, and rivaroxaban for thrombosis prevention in patients undergoing major orthopedic surgery (e.g., total hip arthroplasty or total knee arthroplasty, but not hip fracture surgery); for patients with acute deep vein thrombosis (DVT) In patients with DVT, rivaroxaban may be recommended as the initial anticoagulant therapy.
Table 3 Trials evaluating new oral anticoagulants for prevention of venous thromboembolic events
Note: (+) indicates that the trial results indicate that NOACs are effective and safe; (-) indicates that NOACs are less effective/safe; VTE: venous thromboembolism; DVT: deep vein thrombosis. See Table 2 for the remaining notes
5 Novel oral anticoagulants in patients with acute coronary syndromes not associated with atrial fibrillation
Although the large-scale ATLAS-ACS2TIMI51 trial showed that adding rivastigmine to standard antiplatelet therapy reduced cardiovascular death, myocardial infarction, and stroke events in patients with ACS, it was accompanied by an increased risk of bleeding, with little overall patient benefit. In addition, the RE-DEEM and APPRAISE2 trials showed that dabigatran and apixaban, respectively, did not reduce the risk of cardiac ischemic events in patients with ACS, but instead increased the risk of bleeding. Therefore, the FDA and EMA have not yet approved NOACs for antithrombotic therapy in ACS.
6 Conversion between new oral anticoagulants and traditional anticoagulants
The transition from conventional anticoagulant warfarin to NOACs requires full consideration of the pharmacokinetic and pharmacodynamic characteristics of different types of NOACs (see Table 1). In addition, patients anticoagulated with regular heparin or low-molecular-weight heparin can be directly transitioned to NOACs, but when transitioning from NOACs to warfarin, both need to be Overlapping application until the INR reaches the target value before stopping NOACs, which usually takes 5-10 days.
7 Management of bleeding complications
Patients with an increased risk of bleeding with NOACs should be alerted to the following conditions: accidental overdose of NOACs, concomitant administration of drugs that interact with NOACs, or relative overdose of NOACs due to impaired renal function. If an overdose is suspected, given that most NOACs have a half-life of about 12 hours, close observation of the patient is all that is needed until bleeding complications occur, and if necessary, oral activated charcoal can be administered within 2 to 4 hours of the accidental dose to reduce drug absorption.
There are no effective antagonists against NOACs. For patients with non-fatal bleeding, in addition to local hemostatic measures, patients taking dabigatran can be treated with diuretics to promote its excretion; other therapeutic measures include rehydration therapy, transfusion of red blood cells, platelets or fresh frozen plasma if necessary, and tranexamic acid and desmopressin can be considered for suitable patients.
In addition, dabigatran can be cleared by hemodialysis, whereas direct Xa antagonists cannot be significantly reduced by dialysis due to their high plasma binding rate (see Table 1). In case of fatal bleeding events in patients, prothrombin complex and coagulation factor VIIa preparations may be considered, but there is a lack of sufficient evidence-based medical evidence for their effectiveness.
In conclusion, NOACs represented by rivaroxaban, apixaban, and dabigatran have shown greater advantages compared with warfarin, bringing new hope for patients with thromboembolic disease and atrial fibrillation. the introduction of NOACs heralds the advent of a new era of anticoagulation and antithrombotic therapy, and as long as the clinical application of these drugs can be standardized to maximize their efficacy and minimize the risk of complications, NOACs are expected to NOACs are expected to replace conventional warfarin as the first-line anticoagulant and antithrombotic therapy.