Medical workers are increasing the use of Non-Vitamin K Antagonist Oral Anticoagulant (NOAC) therapies to keep people with atrial fibrillation from falling into a stroke.

Atrial fibrillation patients who underwent percutaneous coronary intervention (PCI) procedure must take antiplatelet agents to prevent stent thrombosis, and also need separate anticoagulation to prevent strokes. That is, atrial fibrillation patients who underwent PCI procedures must take both antiplatelet agents and anticoagulants, exposing themselves to higher risks of hemorrhage.

That shows why the use of NOAC treatments is increasing, which have similar anticoagulating effects to warfarin and are safer than the latter.

What kind of anticoagulation treatments should doctors apply to patients who underwent the PCI procedure, then? To know the answer, Korea Biomedical Review had an interview with Professor Kim Hyo-soo at Seoul National University Hospital, the highest authority on the subject in Korea.

Professor Kim Hyo-soo explains about the new anticoagulation methods for patients who underwent PCI procedures, during a recent interview with Korea Biomedical Review.

Question: Foreign media reports have recently pointed out that among the NOACs in the U.K., the prescription rate of rivaroxaban and apixaban to incompatible patients was increasing, calling for caution.

Answer: Although doctors prescribe NOAC for many patients because of its high safety, drugs should be prescribed with reduced amounts or should not be prescribed at all, depending on patients’ renal functions. I think the media reports were warnings against doctors who prescribe without deeply thinking about of these taboos. Some medicines should not be prescribed or prescribed with half of their amount if the patients’ creatinine clearance (CrCl) index 15, 30 or 45.

In Korea now, the criterion for the insurance coverage of NOAC is CHA2DS2-VASC Score of 2 or higher. If an atrial fibrillation (Afib) patient has a CHA2DS2-VASC Score of 0 or 1, they can’t be covered for NOAC.

Q: For patients who have both atrial fibrillation (Afib) and acute coronary syndrome (ACS), doctors usually prescribe NOAC, together with antiplatelet agents. Is any research underway for three-drug complexes?

A: There have been no established standards for prescribing medicines for Afib patients who underwent PCI procedures. To prevent the clotting of blood in the left atrium which causes brain embolism in patients with atrial fibrillation, the patient must take warfarin. As platelets are the main reason for blood clots in the artery, however, the patients need to take antiplatelet agents like aspirin and clopidogrel additionally. But there were also concerns about hemorrhage if the patients take three drugs at once. This is the reason some doctors prescribe dual antiplatelet therapy (DAPT) for patients with atrial fibrillation without using warfarin. On the other hand, those who believe anticoagulation is more important, used the three-drug complexes by prescribing both warfarin and DAPT.

There was a study called WOEST that compared triple therapy of warfarin and DAPT with double therapy of warfarin and clopidogrel. The results showed that the triple therapy could not reduce the number of ischemic events even though there were lots of hemorrhages because of the aspirin. To sum up, double treatment therapy reduced the risk of bleeding and ischemic events, so the method of prescribing warfarin and clopidogrel proved better. WOEST study has the limitations of “open study” and “single centetrial,” but it did help to promote the double therapy’s excellence.

In recent 'real-world practice,' doctors start with the triple treatment of warfarin and DAPT and discontinue aspirin at specific points. For example, if patients used multiple stents amid a low risk of bleeding, doctors apply tripe treatment for about six months and switches to double treatment. If patients used a single stent and had a high risk of bleeding, however, doctors adopt a more flexible method of using the triple therapy for about a month and changing to the double therapy. Two of the drugs mentioned here used to be warfarin and aspirin previously, but recently doctors often use warfarin and clopidogrel, influenced by the WOEST research.

Q: There are also various opinions as to when doctors should stop using antiplatelet agents, behind which seem to be concerned about hemorrhage.

A: According to doctors’ advice, patients can discontinue the use of all antiplatelet agents after a year and use the monotherapy of warfarin for life. Some medical workers who remain uncertain about prescribing warfarin alone, however, maintain the double therapy of warfarin and clopidogrel, and gradually reduce the dosage of warfarin. In other words, to prevent hemorrhage, they tend to prescribe by lowering warfarin to INR (internationally normalized ratio) 1.5-2.5 instead the usual 2-3.

This notwithstanding, taking warfarin and clopidogrel for a lifetime raises concerns about bleeding as well as the risks of thrombosis and embolism because of the lowered dosage of warfarin. That is why we need to use NOAC, which are safer and show more consistent effects. For simple Afib patients who did not undergo PCI procedure, doctors can prescribe warfarin or NOAC alone. In the case of the monotherapy of warfarin alone, they can control the dosage to INR 2-3, and do not need to switch to NOAC.

My medical principle is not to change to NOAC if symptoms are controlled well by warfarin, to save insurance funds and reduce the patients’ financial burdens. However, if patients use stents and take warfarin and aspirin, or clopidogrel, they have the risks of bleeding if the dosage of warfarin exceeds the criteria even a little. On the other hand, when they reduce warfarin for safety, it may lead to thrombosis or embolism. In this regard, the value of NOAC is highlighted for Afib PCI patients. This is because it is safe and shows consistent effects. And as Afib PCI patients have to take more drugs than simple Afib patients, the former group needs NOAC more urgently than warfarin.

Q: Is it necessary for patients who underwent stent insertion to control the dosage of NOAC?

A: During the first one, three and six months, the decision is up to the doctor to use triple-drug therapy. There had been no data as to whether doctors can reduce to the double therapy in the early stage, what the optimal dosages of NOAC are when they use the double therapy, and how much NOAC they should reduce in the triple therapy.

As a solution, a group of researchers has conducted a study called the PIONEER on the anticoagulation effects and safety of NOAC by dividing Afib PCI patients into three prescription groups and announced its results. The three prescriptions were: a double therapy with the high dose of Rivaroxaban and clopidogrel, a triple therapy with the low dose of Rivaroxaban and DAPT, and a triple therapy with warfarin and DAPT.

The study found that the double treatment therapy had good results. In the triple therapy using warfarin, the risk of hemorrhaging is about 26 percent a year, but in the double or triple therapy using Rivaroxaban, the risk of hemorrhaging stopped at 17 percent. Thus, using NOAC, compared with warfarin, can reduce the risk of bleeding that can occur in the early stage.

Dosage for dabigatran is set at 100mg BID and 150mg BID and is commonly used with clopidogrel, effient, or brilinta as a double treatment. The RE-DUAL study on PCI/Af patients tested three different methods -- warfarin triple treatment, double treatment with low-dosage dabigatran and clopidogrel, and another double therapy, with high-dosage dabigatran and clopidogrel (they used only low-dosage double therapies for elderly patients). As the result of comparing their hemorrhaging risks for two years, double therapy with low-dosage dibigatran produced a better outcome than triple treatment with warfarin. That is why the former method is widely used for the early-stage treatment of patients who underwent stent insertion procedure.

Q: So is the trend changing to the double therapy with NOAC and clopidogrel for patients who had PCI procedures?

A: That’s right. Up until now, the consensus has been to use the triple treatment that includes warfarin for the first six months. In the PIONEER study, however, researchers used the double therapy of high-dosage rivaroxaban and clopidogrel from the beginning, and the RE-DUAL study also confirmed the effectiveness and safety of the double therapy of dabigatran and clopidogrel. Therefore, the formula of the triple therapy that includes warfarin will likely collapse, giving rise to a new guideline.

The existing guideline has been to use the triple therapy of warfarin, aspirin, and clopidogrel for one, three and six months, and then change to double therapy of warfarin and clopidogrel or aspirin. According to recent research results, however, the double therapy that replaces warfarin with NOAC and uses it with clopidogrel has proved its efficacy. Accordingly, I think the current guideline that calls for changing to monotherapy of warfarin after one year of prescription can switch to a new guideline which combines NOAC with clopidogrel.

If you use NOAC with antiplatelet agents, there are risks of hemorrhage, but the risk is lower when compared to warfarin-based therapy. Afib/PCI patients have a high chronic thrombotic ischemic risk and require additional medicine, which is why they must run the risk of hemorrhage compared with simple Afib patients. But the new guideline will be able to reduce the risk of bleeding to nearly a half.

Q: Are you participating in a NOAC study yourself?

A: I participated in AUGUSTUS study which focused on Apixaban, and am currently part of ENTRUST AF-PCI study based on edoxaban. In the ENTRUST AF-PCI study, we are using the single dose of 60-mg edoxaban daily, and we use the double therapy with the P2Y12 antagonist, which is similar to clopidogrel. After a 12-month study, we plan to integrate the examples of grave hemorrhage and those of light but clinically significant bleeding and compare their results.

Q: Could you be more specific about ENTRUST AF-PCI study design? And how do you predict its results?

A: ENTRUST AF-PCI study has a simpler design compared to other similar studies. We are comparing the outcome of two groups: one group follows the existing guideline and uses the warfarin-based triple therapy for one year, and the other group uses the double therapy of edoxaban 60mg and clopidogrel. We are watching whether there are major or minor bleedings after one year of treatment. If a patient’s renal function is weak, has subpar weight or interaction with other medicines, we use edoxaban 30mg for the patient. Given the control group is a relatively simple protocol, including the existing triple therapy that includes warfarin and the research results of edoxaban so far, we expect the ongoing research will be able to reduce hemorrhage risk by about 40 percent.

Q: People say there are not many differences concerning anticoagulation effects, efficacy and hemorrhaging risks among NOACs released in the market so far.

A: The biggest difference among NOACs is the dosage. Patients should take exodaban and rivaroxaban once a day, but they have to take dabigatran and apixaban twice per day.

Right now the interesting point is the post-market register data, as it allows us to experience efficacy and safety in a more varied group of patients than the cases of RCT. When we compared three front-running products in the post-market register data, apixaban had the best results regarding safety, efficacy and bleeding risk, followed by dabigatran and rivaroxaban. In the case of the latecomer exodaban, its Pk/Pddynamics against BID is the same, despite the patients’ taking of QD.

As a result, edoxaban has proved its safety and effectiveness. It is also a once-daily, single-dose drug, and will probably be competing against the market leader rivaroxaban. During the ENGAGE-AF study, exodaban was the only product that reduced all-cause mortality in the Asian data and can be used for patients who have CrCl levels of 15 or higher.

Q: What should be considered when prescribing NOAC?

A: The first to consider is medication adherence. Usually, patients and doctors alike prefer once a day dosage over twice per day, so edoxaban and rivaroxaban take advantageous positions in this regard. On the other hand, dabigatran and apixaban are twice per day dosages, but they have the advantages of showing steady effects concerning pharmacological actions. If there are other medicines taken twice a day, it will not be difficult to prescribe dabigatran and apixaban.

The second is the side effect, and the third is clinical data, but all four drugs are similar on these points.

In the case of emergency surgery, an antagonist is needed, and dabigatron is most advantageous in this regard because its antagonist is in the market. But rivaroxaban is leading the market because it has preempted many indications by conducting aggressive and massive clinical trials, as the front-runner who won recognition in preventing DVT and other matters.

pkt77@docdocdoc.co.kr

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