As a thromboprophylactic agent for long-term cardiovascular disease, vitamin K antagonists represented by warfarin have been the only and irreplaceable agents since their introduction in the 1940s. Its effectiveness has been confirmed by more than half a century of clinical results, but at the same time, its drawbacks have been exposed: narrow therapeutic dose range, susceptibility to under- and over-anticoagulation, large dose variation between patients, large dose variation between periods in the same patient, and anticoagulant strength influenced by multiple drugs and foods. The time in therapeutic range (TTR) is an important indicator of a patient’s time to achieve the desired anticoagulant strength, which is difficult to avoid because of the many factors that interfere with the anticoagulant strength of warfarin. The TTR is typically 60-65%, and for every 10% increase in TTR, the patient’s all-cause mortality rate can be reduced by 29%. Patients receiving prosthetic mechanical heart valves, where the mechanical valve itself is a high risk factor for thrombosis, combined with the fact that many patients have atrial fibrillation, a history of left atrial thrombosis, a history of embolism, cardiac enlargement, and poor cardiac function, are among these risk factors, making their requirements for anticoagulation therapy much higher than those of patients with atrial fibrillation alone or venous thrombosis prophylaxis after orthopedic surgery. The coagulation process and the point of action of anticoagulant drugs To date, the direct thrombin inhibitor that has been more intensively tested in clinical trials is dabigatran (Dabigatran, trade name Pradaxa, Boehringer Ingelheim, Germany). The coagulation factor Xa inhibitors are Rivaroxaban (Xarelto, Bayer, Germany) and Apixaban (Eliquis, Bristol-Myers Squibb, USA). The new vitamin K antagonist is Tecarfarin, ARYx Therapeutics, Inc. Dabigatranate is hydrolyzed immediately after oral administration to produce dabigatran with anticoagulant activity, reaching peak plasma concentration and maximum anticoagulant effect 2-3 hours after administration, and this two correlate well. The bioavailability of the oral drug is low, at 6.5%. 80% of dabigatran is excreted as a prototype via the kidneys and the rest via the biliary tract. In individuals with normal renal function, the plasma half-life is 11-22 hours, with a mean of 13 hours. The anticoagulant effect of the drug is prolonged in the presence of moderate or greater renal impairment, and dabigatran is contraindicated in patients with renal failure. Dabigatran and dabigatran esters are not metabolized by cytochrome P450 and do not affect the activity of this enzyme, so the drug is not affected by the metabolism of other drugs or food. The anticoagulant effect of dabigatran can be affected by other pathways by etanercept, quinidine and verapamil. The plasma protein binding of dabigatran is only 35% (90-95% for warfarin), and the pharmacokinetics of this drug are not affected by competition for plasma protein binding from other drugs. Food delays peak plasma concentrations by approximately 2 hours, but has little effect on the anticoagulant effect. Animal studies have shown that dabigatran has reproductive toxicity. The anticoagulant effect of dabigatran can be measured by the Thrombin Clotting Time (TT), Ecarin Clotting Time (ECT), Prothrombin time (PT, which can be converted to INR), and Activated Partial Thromboplastin Time (aPTT) tests, the first two being slightly more sensitive. Due to the short half-life of the drug, the values of the blood specimens tested at different times after the administration of the drug can vary significantly. More importantly, it is unknown how long these times should be for patients who require different anticoagulation strengths. Dabigatran is currently approved in the European Union, Canada, and the United Kingdom for the prevention of deep vein thrombosis after lower extremity joint replacement surgery. Clinical trials that have been completed or partially completed are thromboprophylaxis in patients with atrial fibrillation, treatment of deep vein thrombosis, and treatment of thrombotic complications after acute coronary syndrome. In a mechanical valve anticoagulation trial in pigs, dabigatran was found to have a preventive effect on valve thrombosis, but this trial was observed for only 30 days at high doses of dabigatran, up to 20 mg/Kg per dose, twice daily. Case reports of dabigatran applied to anticoagulate patients with mechanical valves in special circumstances have begun to be reported clinically, with poor results and patients developing multiple cerebral embolisms and being forced to return to warfarin anticoagulation instead. Among the many saban (rivaroxaban, apixaban, edoxaban, LY517717, betrixaban, TAK 442, YM150, otamixaban) agents under development and investigation, those in more advanced clinical trials and with potential for long-term anticoagulation in prosthetic valves are currently rivaroxaban and apixaban. Both drugs are direct inhibitors of coagulation factor Xa. A comparison of the two is shown in the table below. Oral rivaroxaban has a high bioavailability of 80% and a plasma protein binding rate of 92-95%.CYP3A4 and P-glycoprotein inhibitors and CYP3A4 inducers (e.g., ketoconazole, rifampin) can enhance and diminish the anticoagulant effect of rivaroxaban, respectively. Rivaroxaban also has reproductive toxicity. There are no reports of animal studies or clinical applications of saban analogs for prosthetic valve anticoagulation. As of now, the US Federal Food and Drug Administration (FDA) has not approved clinical trial applications for rivaroxaban for thrombosis prevention in patients with atrial fibrillation. RE-ALIGNT, a clinical trial in Europe looking at dabigatranate Pradaxa for anticoagulation in patients with mechanical valves, has recently been terminated, and the incidence of stroke, infarction, prosthetic valve thrombosis and bleeding was higher in patients receiving Pradaxa anticoagulation than in those receiving warfarin anticoagulation. Accordingly, the FDA issued a safety statement on December 19, 2012, requiring Pradaxa anticoagulation to be disabled for patients with mechanical valves. Both of these new anticoagulants have stable pharmacokinetics, are much less affected by other foods and drugs than vitamin K antagonists, have stable anticoagulation strength at fixed doses, and do not require routine monitoring. There are several major problems facing clinical application: 1. The short half-life, which generally requires twice daily dosing, is certainly inconvenient for long-term anticoagulation therapy. 2. At present, for these drugs, there are no antagonists, and when way drug overdose, the main method is to wait, using the feature of short half-life of the drug, and wait for the effect of the drug to disappear by itself. Taking activated charcoal can significantly reduce drug absorption. In emergency situations, the patient can be infused with human prothrombin complex, genetically recombinant human factor VII or hemodialysis (high plasma protein binding rate of rivaroxaban makes dialysis ineffective). 3, the anticoagulation strength of drugs is not uniformly tested, and people do not yet know which method should be used to test the anticoagulation strength of these drugs most accurately and what the range of values should be for each disease requiring anticoagulation therapy. These data must be obtained after a long period of time, a large number of patients, different patients (age, gender, disease, ethnicity, the function of each organ, etc.) clinical application to arrive at. 4. Expensive. The domestic price of Bactrim 10 mg X 5 tablets is $160 and the foreign price of 10 mg X 60 tablets is $510. The foreign price of Pradaxa is $160 for 150 mg X 60 tablets. Tecarfarin is approved in Canada and EU for the prevention of venous thrombosis after orthopedic surgery. Tecarfarin has a similar chemical molecular structure to warfarin, being a single mirror image (warfarin has S-isomer and R-isomer), and its anticoagulation mechanism is exactly the same as warfarin, so the anticoagulation strength and monitoring methods are also the same. two main differences between Tecarfarin and warfarin are: one is its long half-life of 107-140 hours, with an average of 119 hours (40 hours for warfarin); secondly, Tecarfarin is metabolized by carboxylesterase and does not pass through the hepatic cytochrome P450 (CYP450) system, so it is not affected by changes in CYP450 activity due to food, metabolism of other drugs, or ethnic differences as warfarin is. Therefore, the development company hopes that Tecarfarin may increase TTR, and the results of the recent preliminary clinical trial (Phase IIA) showed an increase in TTR during the patient’s phase of Tecarfarin compared to warfarin, especially if the patient was also on a CYP2C9 inhibitor. Based on the current results, it will be many years before we can determine whether these drugs can be used safely and effectively in patients receiving mechanical prosthetic heart valves. Whether we are now seeing a real silver lining or a fleeting trail of shooting stars across the night sky is still unknown. The ideal anticoagulant drug should meet the following requirements: 1, there is a real anticoagulant effect, can effectively prevent the occurrence of all the need to prevent thrombosis; 2, in sufficient anticoagulant strength, does not occur than the vitamin K antagonist fatal bleeding; 3, drug half-life is long, after the administration of anticoagulant effect lasting and stable; 4, no need to routinely monitor the anticoagulant strength, if monitoring, the method is simple and accurate results 5, the presence of effective antagonists, can quickly eliminate its anticoagulant effect in a short period of time; 6, no other toxic and side effects; 7, no effect on fetal development and reproductive process, does not enter the breast milk, no effect on the nursing infant; 8, anticoagulant strength is not affected by food, other drugs, the patient’s age, ethnicity and the patient’s liver and kidney function status; 9, the price is cheap. If such a drug emerges, some basic issues of heart valve surgery will have to be reconsidered.