Atrial fibrillation (AF) is one of the most common cardiac arrhythmias. Thromboembolic complications are the leading cause of death and disability in AF, and stroke is the most common type of presentation. Atrial fibrillation is an independent risk factor for stroke, and having atrial fibrillation increases the risk of stroke fivefold. The rate of death, disability and recurrence of stroke due to AF is very high, which imposes a serious economic burden on patients and society. Anticoagulation plays an important role in stroke prevention in atrial fibrillation, and the reasonable use of anticoagulants can significantly reduce the incidence of ischemic stroke. However, anticoagulation therapy for patients with atrial fibrillation in China is significantly inadequate. The traditional anticoagulant warfarin requires regular monitoring of coagulation-related indicators and dose adjustment, and interacts with a variety of drugs and/or foods, limiting its widespread clinical use.
The new oral anticoagulants have the advantages of rapid onset of action, predictable efficacy, and no need for routine coagulation monitoring and routine dose adjustment. Among them, the direct factor Xa inhibitor rivaroxaban is approved for stroke prevention and non-CNS systemic embolism in patients with non-valvular atrial fibrillation in China.
I. Mechanism of action and pharmacological characteristics of rivaroxaban
Factor Xa is a key link between endogenous and exogenous coagulation pathways and is the first step in the common coagulation pathway. factor Xa inhibitors reduce thrombin production, but do not affect the activity of thrombin already produced, and have little effect on physiological hemostasis.
Rivaroxaban specifically and directly inhibits free and bound factor Xa, blocks thrombin generation and inhibits thrombosis; it is rapidly absorbed orally, and both rivaroxaban 15mg and 20mg should be taken with meal, and almost completely absorbed. 1/3 of the active prototype drug is cleared by kidney, 2/3 is metabolized into inactive metabolites and excreted through feces and urine. Rivaroxaban can effectively inhibit thrombin production for 24h.
II. Population and dosage of rivaroxaban
For patients with non-valvular atrial fibrillation with CHADS2R1 (with any of the following: congestive heart failure, hypertension, age R75 years, diabetes mellitus, history of stroke or transient ischemic attack) and no contraindication to anticoagulation, rivaroxaban 20 mg, 1 time/d is recommended. for patients with creatinine clearance (Ccr) 30~49 ml/min, 15 mg, 1 time/d is recommended. for patients with For patients with Ccr15~29 ml/min, anticoagulation therapy should be given with great caution, and if needed, 15 mg,1 time/d.
Contraindications
Rivaroxaban is contraindicated in patients with hypersensitivity to rivaroxaban or any of the excipients in the tablet; active bleeding; hepatic impairment with coagulation abnormalities and risk of bleeding, including hepatic cirrhosis of Child-Pugh grade B and C; pregnant and lactating women; Ccr<15 ml/min; platelets below 20×109/L.
IV. Detection of anticoagulant activity of rivaroxaban
Clinical trials have confirmed that rivaroxaban has good predictability of anticoagulant effect, wide therapeutic window, no accumulation after multiple doses, few interactions with drugs and food, and no need for routine monitoring of coagulation indexes. However, a significant prolongation of prothrombin time (PT) in patients taking rivaroxaban may indicate an increased risk of bleeding.
Although routine monitoring of coagulation function is not necessary when taking rivaroxaban, in special cases, such as suspected overdose, emergency surgery, serious bleeding events, need for thrombolysis or suspected poor compliance, the anticoagulant effect of rivaroxaban and the risk of bleeding can be assessed by measuring factor Xa activity or PT by sensitivity reagents, and the time of blood collection should be indicated when measuring.
V. Evidence from studies of rivaroxaban for stroke prevention in non-valvular atrial fibrillation
VI. Use of rivaroxaban in special circumstances
(i) Surgical period
1. Preoperative period: For patients taking long-term rivaroxaban, if elective surgery is proposed, it is recommended to discontinue rivaroxaban for 24h after surgery.
If emergency surgery is required, rivaroxaban should be stopped for at least 12h (preferably 24h); if you cannot wait for 12h of discontinuation to proceed, you can test for anti-Xa activity and weigh the bleeding risk and the need for emergency surgery.
Discontinuation is not required for low-bleeding-risk procedures, such as body abscess incision or simple tooth extraction (no more than 3 teeth). However, try to avoid invasive operations 2~4h after rivaroxaban administration.
2.Postoperative: After surgery (elective or emergency surgery) or invasive operation, if the clinical condition is stable and hemostasis is adequate, rivaroxaban administration can be resumed 8~12h after surgery without bridging with other anticoagulants.
3. Axial anesthesia (both spinal and epidural): Anticoagulation may increase the risk of epidural or subdural hematoma during axial anesthesia (spinal/epidural anesthesia) or spinal/epidural puncture. Patients should be off the drug for at least 24 h. Otherwise, axial anesthesia is not recommended and should be replaced with general anesthesia. In patients undergoing invasive puncture (e.g. lumbar puncture), rivaroxaban administration needs to be delayed for 24h.
4. Indwelling epidural catheter: Rivaroxaban is not recommended for patients with postoperative indwelling epidural catheter who are at risk of epidural or subdural hematoma with anticoagulation therapy.
(ii) Special patients
1. Advanced age: Advanced age (R75 years) is an important risk factor for both thromboembolism and bleeding.
For elderly patients with normal renal function, 20mg, 1 time/d is recommended; for elderly patients with CcrR50ml/min, 20mg, 1 time/d is recommended; for elderly patients with Ccr30~49ml/min, 15mg, 1 time/d is recommended, and renal function should be monitored regularly.
The recommended dose for patients aged R75 years and weighing ≤50kg is 15mg, 1 time/d.
2, Patients with high bleeding risk: For patients with HAS-BLED score R3, the recommended dose is 15 mg, 1 time/d.
3, Renal insufficiency.
Mild renal insufficiency (Ccr50~80ml/min): dose 15mg, 1 time/d, annual review of renal function is recommended.
Moderate renal insufficiency (Ccr30~49ml/min): dose 15mg, 1 time/d, suggest to review renal function every six months.
Severe renal insufficiency: (Ccr15~29ml/min): use rivaroxaban with caution, if needed, dose 15mg, 1 time/d, and it is recommended to review renal function every 3 months.
Ccr<15ml/min, rivaroxaban is not recommended; for those who have used the drug, if renal function deteriorates to Ccr<15ml/min, the drug should be discontinued.
4. Abnormal liver function: No dose adjustment is required for patients with mild liver impairment (Child-Pugh classification A).
Rivaroxaban is contraindicated in patients with hepatic disease with coagulation disorders and high risk of bleeding, including patients with cirrhosis (Child-Pugh classification B and C).
5. Patients with non-valvular atrial fibrillation combined with acute coronary syndrome (ACS) and/or percutaneous coronary intervention (PCI).
(1) Patients with atrial fibrillation with episodes of ACS.
Patients with non-valvular atrial fibrillation taking rivaroxaban should be suspended from rivaroxaban and given dual antiplatelet therapy (DAPT) in the event of an ACS. However, aspirin only should be given first in patients at high risk of bleeding, and DAPT therapy should be considered 24 h after rivaroxaban discontinuation.
In patients with acute ST-segment elevation myocardial infarction (STEMI), thrombolytic therapy is not recommended and direct PCI is strongly recommended; however, if thrombolytic therapy is the only option, other anticoagulation should be given after 24 h of rivaroxaban discontinuation: e.g., normal heparin (UFH), low molecular heparin (LMWH), and sulfadoxine sodium.
In patients with non-ST-segment elevation acute coronary syndrome (NSTE-ACS), coronary angiography and intervention should be performed 24 h after rivaroxaban discontinuation, if possible.
For patients preparing for PCI: transradial route is recommended to reduce the risk of bleeding at the puncture site; balloon angioplasty or bare metal stent (BMS) is recommended if indicated or allowed to reduce the need for (long-term) triple therapy; intraprocedural intravenous anticoagulation can be given simultaneously, bivalirudin is recommended but should be stopped immediately after the procedure; glycoprotein (GP) IIb/IIIa should be avoided as much as possible antagonists; the duration of postoperative dual or triple therapy should be minimized.
For patients with multiple lesions, cardiac bypass grafting is recommended to avoid long-term triple therapy.
(2) Long-term treatment of atrial fibrillation combined with ACS.
For patients with non-valvular disease combined with ACS who have not undergone PCI, single-combination antiplatelet agents such as clopidogrel combined with warfarin can be chosen. If PCI is performed, triple or dual antithrombotic therapy (antiplatelet combined with anticoagulation) is recommended according to the clinical situation. The duration of triple therapy should be minimized [1 month of treatment after bare metal stent placement is recommended; 3 months and up to 6 months for drug-eluting stents (DES)], unless the patient is at high residual risk for ischemic events. Thereafter, single-combination antiplatelet therapy combined with warfarin therapy may be considered. There is a lack of research evidence in this area for rivaroxaban, but rivaroxaban can be combined with a single antiplatelet agent.
(3) Stable coronary artery disease (CAD): For the treatment of new-onset atrial fibrillation in patients with CAD, warfarin anticoagulation alone may be given, and combination antiplatelet therapy is not recommended. Rivaroxaban can be used as an alternative drug to warfarin.
6. Cardioversion and/or radiofrequency ablation for non-valvular atrial fibrillation.
It was found that there was no statistically significant difference in long-term stroke incidence and survival between the use of rivaroxaban and warfarin in patients with cardioversion and radiofrequency ablation.
7. Non-valvular disease combined with acute ischemic stroke.
(1) Acute phase: For those within 48 h of rivaroxaban administration, recombinant tissue-type fibrinogen activator (rt-PA) thrombolysis is not recommended and interventional therapy for hemodynamic reconstruction may be considered.
(2) Recovery period: If the infarct size is small and there is no risk of secondary intracranial hemorrhage, rivaroxaban therapy can be continued. It is recommended to follow the 1-3-6-12 principle: rivaroxaban therapy can be given 1 d after TIA, 3 d after mild infarction, 6 d after moderate infarction, and 12 d after severe infarction.
(iii) Conversion between anticoagulant drugs
1.Conversion from warfarin to rivaroxaban: stop warfarin first and monitor INR closely. rivaroxaban can be given immediately when INR≤2.0, between 2.0~2.5, rivaroxaban can be given on the next day, and continuous monitoring of INR when it is >2.5.
2. Switch from rivaroxaban to warfarin: overlap two drugs, take warfarin in the morning (warfarin starts from standard dose), take rivaroxaban at dinner, test INR before the next dose of rivaroxaban, stop rivaroxaban when INRR 2.0. Adjust warfarin dose according to INR within the first month.
3. Conversion with intravenous or subcutaneous anticoagulant: for those who use LWMH and sulforaphane sodium, rivaroxaban should be given at the next injection of anticoagulant; for those who use intravenous normal heparin, rivaroxaban can be given after stopping; if rivaroxaban is converted to injectable anticoagulant, it should be started at the next administration of rivaroxaban.
(iv) Combined medication
1. The combination of rivaroxaban with other anticoagulants and antiplatelet agents can increase the risk of bleeding. It must be used with caution after assessing the benefit-risk. Rivaroxaban can be combined with low-dose aspirin (≤100mg/d), and the combination of rivaroxaban and dual antiplatelet is not recommended.
2. The combination of rivaroxaban and non-steroidal anti-inflammatory drugs may increase the risk of bleeding.
VII. Adverse reactions of rivaroxaban and principles of treatment
The main adverse reactions are bleeding. Severe bleeding is manifested as gastrointestinal bleeding, sarcoid hematuria, etc.; life-threatening bleeding such as intracranial bleeding, etc. The annual incidence of severe bleeding is <1%. Other common adverse reactions include nausea, elevated liver enzymes, minor bleeding (rhinorrhea, gum bleeding, bruising, increased menstruation, etc.).
1. Prevention: Care should be taken to assess the patient’s risk of bleeding. High bleeding risk may benefit more from a reduced risk of stroke. Correctable risk factors for bleeding should be actively improved, such as good control of blood pressure, regular assessment of renal function, minimization of combination medications (e.g., antiplatelet agents and nonsteroidal anti-inflammatory drugs), and close clinical monitoring.
2. Treatment.
When mild or local bleeding occurs, first delay or suspend drug administration and perform local compression to stop bleeding.
Discontinue rivaroxaban for severe bleeding; activated charcoal or gastric lavage may be given. Local compression, assess the need for surgery, and give rehydration, blood transfusion, and hemodynamic support therapy. Give prothrombin complex concentrate (PCC), fresh frozen plasma (FFP), recombinant coagulation factor VIIa (rFⅦa) if necessary.
Life-threatening bleeding: Discontinue rivaroxaban; if possible, surgical hemostasis should be performed; meanwhile, give supportive treatment such as rehydration, blood transfusion, hemodynamics, and actively give PCC, FFP and other hemostatic treatment.
3. Drug overdose management: Patients should first be evaluated for bleeding. For patients without bleeding, activated charcoal or gastric lavage can be used for a short period of time after drug administration, and relevant coagulation indexes should be monitored; if bleeding occurs, refer to the management of bleeding.
VIII. Long-term management of patients
Patients should be followed up 1 month after receiving rivaroxaban anticoagulation therapy and every 3 months thereafter. Patient follow-up in the anticoagulation specialty clinic is recommended.
IX. Current status and outlook of rivaroxaban in the treatment of cardiovascular diseases
Rivaroxaban is now widely used worldwide for venous thromboembolism (VTE) prophylaxis after elective hip and knee arthroplasty, stroke and systemic embolism prophylaxis in patients with non-valvular atrial fibrillation, as well as VTE treatment and secondary prevention. Rivaroxaban may simplify anticoagulation and improve clinical prognosis in patients with non-valvular atrial fibrillation compared with conventional anticoagulation therapy.