New anticoagulation drugs more effective in stroke prevention

Although ten times pricier, these new generation drugs prove to be cost-effective
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Dr. PP Mohanan

Director and HOD of Cardiology

Westfort Hi-Tech Hospital Thrissur, Kerala

Dr. NN Khanna

Interventional Cardiologist

Apollo Hospital, New Delhi

Dr. HK Chopra

President, Cardiological Society of India

Moolchand Hospital

Atrial Fibrillation (AF) is a condition in which the heart doesn’t beat rhythmically. Dr. PP Mohanan attributes its rising prevalence to the elderly population’s vulnerability towards it, which constitutes 12% of India.In this conversation with Dr. HK Chopra, President, CSI, he also discusses different oral anticoagulant drugs available for stroke prevention- the most dangerous consequence of AF. “The newer generation of these drugs, although way more effective than the older ones like warfarin, are priced ten times higher.”But a cost effective analysis shows that, after costs of routine INR monitoring needed in case of warfarin are considered, the new drugs, which do not require INR check ups, are definitely cost-effective. Another issue of importance brought out by Dr. NN Khanna, Chairman of CSI NIC, is the occurrence of aortic disease in South Asian population ten years earlier than in their western counterparts.“Since ECG doesn’t show any discrepancy, its detection is also difficult unless a CT angiograph is done. When not diagnosed and treated, it puts a person at a 40% risk of dying from a stroke.“With regard to method of operation, Dr. Khanna prefers mechanical intervention over surgical intervention because surgery has a higher rate of mortality.


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Dr. HK Chopra

I have with me Dr. P. P. Mohanan and a very important and pertinent question today’s era, the people are talking of higher prevalence of atrial fibrillation may be the longevity is more now and we have more elderly patients or our patients having more procedures like CABG or multiple angioplasties and stenting or our patients are falling sick to CKD because they are living longer. They have diabetes, diabetic nephropathies, hypertension, and metabolic syndrome and we find gradually the prevalence of stroke is also increasing because of underlying atrial fibrillation. Dr. Mohanan I really like to ask you do you agree with this statement that the prevalence of atrial fibrillation is really rising and #2 what are the modalities by which you diagnose atrial fibrillation where anticoagulants can be prescribed?


Dr. PP Mohanan

You are perfectly right Dr. Chopra about the rising prevalence of atrial fibrillation in our country. I will say that we are an elderly nation with almost 12% of our population being more than 60 years age and we all know that the incidents of atrial fibrillation rises as the age goes on increasing and with the increasing number of people living in 60s, 70s, and 80s, we are definitely going to see more and more number of atrial fibrillation. Generally, it is easy to diagnose with the availability of the Holter monitoring or loop recording systems. It is a simple process to diagnose atrial fibrillation. Many times it may not be permanent or persistent one, it could be an intermittent one, which could be picked up by these Holter recordings or loop recordings. It is sad that many of this people with atrial fibrillation are not treated properly because the only drugs which are useful for stroke prevention, which is one of the main dangers of atrial fibrillation are oral anticoagulant drugs. There is actually no role for antiplatelet drugs in prevention of stroke, but people are little bit of scared when it comes to oral anticoagulant drugs. The only available oral anticoagulants till may be about few years ago four or five years ago had been the vitamin K antagonist groups of drugs, the warfarin and Coumadin, but now the last three or four years we have seen a new generation of newer oral anticoagulant drugs NOACs as they are called as coming into the market which acts either on the thrombin, the factor 2 or in the factor 10 among the calculation factors. So the drugs which cause or inhibit the thrombin or the dabigatran basically; most important being the dabigatran and amongst the factor 10 inhibitors we have three drugs in the form of apixaban, rivaroxaban, and edoxaban. We all know the problems with the use of warfarin because it is a useful drug, but with a lot of limitations. There are a lot of other factors which desire the efficacy of warfarin. Many of them may not come to the required INR level. The INR level has to be in between 2 and 3 for the warfarin to be effective. Many times, it requires regular monitoring. There are many other drugs which interfere with warfarin. There are also genitive factors, which may tell about the efficacy of warfarin, so we have lot of problems with warfarin. So the importance of newer drugs is that it would not need any regular monitoring. It can be more effective. Many of the other drugs, diet will not interfere with its action. So the newer oral anticoagulant drugs have tremendous advantage over warfarin not only in its efficacy, but also its problem with bleeding.


Dr. HK Chopra

I have very important question Dr. Mohanan. You mentioned about thrombin antagonist and you also mentioned about factor 10 antagonist. If we have to choose are they identical in the efficacy and safety or there is a difference?


Dr. PP Mohanan

Well, most of them if you ask me they are almost similar except that, for example the first one was to hit the market was dabigatran. The other three drugs which are available now in our market, we have dabigatran, apixaban, and rivaroxaban right now are available. Edoxaban will be hitting the market soon. These three drugs are almost similar except for example dabigatran is excreted renally, 80% of it is excreted renally, while apixaban is majority it comes through and metabolized through the liver. So if you take the half-life most of them have about 11 to 14 hours. Rivaroxaban is used usually once daily while dabigatran and apixaban has to be given twice daily.


Dr. HK Chopra

Is there any cause difference in the two antithrombotic especially anticoagulants when you are talking about factor 10 inhibitor or thrombin inhibitor, cost difference or they are same cost?


Dr. PP Mohanan

Almost similar cost, but when we compare with our old trusted drug warfarin, there is a phenomenal difference. The major problems of non-usage of these useful NOACs have been its higher cost.


Dr. HK Chopra

How much is the difference.


Dr. PP Mohanan

Almost more than 10 times, more than 10 times.


Dr. HK Chopra

What is the cost?


Dr. PP Mohanan

Dabigatran cost will be about 120 rupees and apixaban will be almost similar while warfarin you will get it may be less than 5 rupees


Dr. HK Chopra

Dr. Mohanan I think lot of our patients who are on warfarin or acenocoumarine, they have to have a periodic INR checkups that also cause money and #2 if we show that the efficacy and safety of newer anticoagulants is higher as compared to the old. So called old is gold, is it really gold, there is lot of doubt in it and #2 we do not have to go for any INR check and I feel if it really prevents the stroke, does the cost matter?


Dr. PP Mohanan

It is a very interesting point you have brought in because the cost effective analysis has shown that that newer oral anticoagulants are definitely cost effective. You said about the INR monitoring and the other factors, which are involved; the better efficacy. All this will definitely give an advantage to the NOACs. The only situation may be if somebody’s INR is well maintained on warfarin, but that happens only about 50% of time or less than 50% of the time in our setting. That is the only situation where one may continue with the conventional warfarin. Otherwise, in all other setting if cost is not a big issue, every atrial fibrillation patient could be put on to the newer oral anticoagulant drugs.


Dr. HK Chopra

I have just one more question, lot of the patients are on so called newer or anticoagulants and if person is comprised from kidney function point of view because most of them are diabetics. Do you have any protocol to chose an oral anticoagulant or antithrombin inhibitor or effective 10 inhibitor or do we require any dose of regulation or there is no dose regulation #1, 0800 #2 lot of elderly patients they are in the 80s or 90s, is the dose requirement is same as compared to 60s or 70 years of age.?


Dr. PP Mohanan

Basically it all depends upon the creatinine clearance. If the creatinine clearance is less than 15, I will not use any of the newer oral anticoagulants. I will go back to the earlier conventional warfarin or the cyanocobalamins, but if it is anything more than 15 again it depends upon the three drugs. Dabigatran is mainly excreted by kidney, so it may be preferable to use either apixaban or rivaroxaban in those setting. If the creatinine clearance is in between 30 and 60, you may use even a smaller dose of dabigatran like 110 mg or again dosage adjustment can be done even in rivaroxaban and apixaban, may be conventionally apixaban is given 5 mg twice daily. You can make it 2.5 mg twice daily.


Dr. HK Chopra

Your message is very clear Dr. Mohanan that if a patient has got end-stage renal disease with a very low EGFR, in such patients we can also give newer oral anticoagulants especially those that are thrombin inhibitors and especially it can be treated through dialysis. All these patients are dialyses twice a week or alternate day and if we prevent the stroke in such patients, why not we should use in these patients?


Dr. PP Mohanan

You are right.


Dr. HK Chopra

So I think it is very important the message is very clear by Dr. Mohanan that newer anticoagulants have definite role and according to him every atrial fibrillation should be given oral anticoagulants of newer nature because we do not need any INR checkups. It can be given in the patients with CKD with a very poor EGFR and he also says we must make sure that he should not become a victim of stroke, which is really very painful and we cannot do when the stroke sets in. I think the message is very clear and we must have a lot of data to support what Dr. Mohanan is saying in the years to come. We are thinking of bringing out a text book on atrial fibrillation and oral anticoagulants very soon.


Dr. PP Mohanan

It may be also good idea to have newer Apps for the patient, an App which can possibly when we are doing away even with INR, but the App can definitely also help in getting better stroke prevention.


Dr. HK Chopra

So I think App is very brilliant idea because it is App which will create more awareness in the doctor’s mind, patient’s mind, and ultimately who is the beneficiary, it is the patient. I think it will create a huge impact not only in the governmental organizations as well as in the private organizations and I feel that there is lot of scope for the newer anticoagulants in the years to come. Thank you very much Dr. Mohanan for your brilliant exposition.


Dr. PP Mohanan

Thank you.


Dr. HK Chopra

We have with us Dr. Anand Khanna who is chairman of CSI NIC. Dr. Mohanan and Dr. Khanna are very well known for tremendous contribution in work in the peripheral vascular intervention and aortic intervention, renal intervention, and carotid interventions. Dr. Khanna, we see a lot of patients these days and they have aortic disease. Do you come across lot of patients of aortic disease because of rising prevalence of obesity and diabetes in a younger age group relatively, elderly of course, you have a number of patients, but elderly, you mention like 50s or 60s and how do you intervene them. Can you give some your intervention data and the success rate?


Dr. NN Khanna

Ya I mean that is a very pertinent question and what we see in India and Southeast Asia like coronary artery disease, the aortic disease especially the aortic dissection and aortic aneurysm comes at least a decade earlier as compared to the Western population. Now if you see the risk factor for developing aortic disease, aorta is the first vessel to develop atheromas, because it gets the maximum stress of blood pressure. If you have high blood pressure and this leads to burrowing and separation of the two layers of aorta and it leads to aortic dissection and it has been shown that in Southeast Asia aortic dissection occurs at least a decade earlier than what happens in the Western populations. There is a definite data that it does occur early. Now, in terms of treatment, many a times it is missed because this is one disease like pulmonary embolism. If you do not have high suspicion index, they are going to miss aortic dissection because they would not do the classical aortic dissections where you have unequal pulses or radial femoral delay and that too many physicians do not see and if you miss it you would just lay them off as acute gastritis because you keep on getting chest pain, the ECG is normal, your troponin I is negative, and you just see the pulses and you say nothing is there. Actually what you should do is you have do if you suspicion you should do a CT angio and there is a test in CT angio called triple rule out. So the triple rule out actually is you do a CT angio and it sees whether you have coronary artery stenosis. It does CT angio of coronary. It looks for pulmonary embolism and acute pneumothorax and it rules out the dissection. So one test which takes just 2 minutes if you do not find that the patient is having chest pain and his ECG is normal or his troponin I is negative, straight away take them to CT angio unit, do a CT angio within 2 minutes you will get to the diagnosis. Because if you miss these patients, you may not get a second chance and the dissection may sort of progress, you may end up with stroke or acute AR or acute coronary event or rupture of aorta.


Dr. HK Chopra

Dr. Khanna, I think you are very eminent interventional cardiologist for peripheral vessels. Do you recommend that intervention has a tremendous role especially the endovascular intervention in the dissection of aorta as compared to what you do initially in surgical intervention. What is the role if you compare in the previous approach and recent approach?


Dr. NN Khanna

As of now, if you have a type B dissection, which means the dissection of the descending thoracic aorta beyond the left subclavian artery, which is the commonest, if you have that the survival rate with early endovascular intervention is much better than surgery because surgery carries a very higher risk of mortality and morbidity. It is a major open heart surgery and this is a very simple percutaneous, now a day totally percutaneous procedure, which is done by a Preclose technique and what you do is just internally seal the tear and the patient recovers to normal health and can be discharged on the second day. As compared to surgery, when we get through open heart surgery, the morbidity is 10%, different complications and mortality is about 5%. So that is a risky operation and the patient usually is very sick because these patients are very sick when they present. So definitely endovascular treatment is a class 1 indication in descending thoracic aortic dissection, but if you have an ascending aortic dissection, then surgery is the treatment of choice and it should be done surgically because we do not have grafts which can actually seal the dissection and also protect the coronaries and the carotids.


Dr. HK Chopra

Dr. Khanna I have two important questions, once subjective patients for endovascular intervention do you put them on anticoagulants or do you put them on long-term antiplatelets or dual antiplatelets. What is the protocol you follow for your patients?


Dr. NN Khanna

Aorta is such a big vessel that the thrombosis is very rare, so what we do is only put them on dual antiplatelets for one month and single aspirin for lifelong, that is all what is required.


Dr. HK Chopra

1600 But if a patient has got associated peripheral vascular disease since most of the patients are diabetics. In the peripheral vascular disease they are also go forward only dual antiplatelets or you prefer to choose newer anticoagulants now?


Dr. NN Khanna

In peripheral vascular disease, if you have atherosclerotic lesions usually not Burger’s type of disease you treat them in the same way as coronary artery disease. You treat them with high doses of statin because these clots are usually inflamed. You give them one antiplatelet at least preferably dual antiplatelet and you give the ACE inhibitors.The antiplatelet of choice in peripheral vascular disease is either cilostazol or clopidogrel if we are using one and if you are choosing two then it has to be aspirin and one of these.


Dr. HK Chopra

In the older times, people used to do a lot of bypass surgeries especially when there is peripheral vascular disease. Do you still find that people are subjected to more surgical intervention or they go only for mechanical intervention and surgical intervention is reduced?


Dr. NN Khanna

If you look at the trials especially the STYLE trial and the TOPAS trial, the endovascular approach for treating lower limb ischemia both in chronic setting as well as in acute setting is much better than surgical approach. The 5-year patency and 1-year patency and the secondary patency is much higher with endovascular approach, but the problem is most of the patients even now come to vascular surgeons and most of them do not know how to do good endovascular procedure, so they would end up putting grafts and these grafts do not last long, but lot of new cardiologists and radiologists started learning this and endovascular approach all over the world is the treatment of choice, that is the way to go.


Dr. HK Chopra

Dr. Khanna I think lot of patients which we see as you mentioned they are elderly and most of these patients we just discussed few minutes ago they have a very high prevalence of atrial fibrillation. So seeing that as comorbidity, atrial fibrillation, the patient has got a peripheral vascular disease or aortic disease or aortoiliac disease. Do not you see that the old anticoagulants prevent the leg stroke or abdominal stroke the way we are seeing cerebral stroke, there is no preference. When the clot is dislodged from the LV or from the LA or from the LA appendage, there is no choice where to go, to go in the brain or go in the periphery or the renal vessels.


Dr. NN Khanna

Definitely. If you have an atrial fibrillation, you have to treat them with oral anticoagulation unless there is a contraindication and as you said the clot can go anywhere, although it tends to go more towards carotid because those are the first vessels, but it can go anywhere and if it goes to the leg, you can lose your leg and if it goes to the kidney you lose your kidney and if it goes to the bowel it is the worse thing and you do not survive.


Dr. HK Chopra

I think it is a beautiful expression by both the learned speakers and they said that atrial fibrillation is a real burning problem, whether it is a disease of carotids 1900 or it is a disease of aorta or disease of peripheral vessels or disease of renal vessels. If there is underlying comorbidity in the heart may be because of metabolic cause or because of cardiac cause, all these patients who have atrial fibrillation they all need newer oral anticoagulants on a long term to prevent the stroke related to the brain or stroke related to the kidney or related to the lower limbs. It is very-very important and the second important point which Dr. Anand Khanna has emphasized is on the need of mechanical intervention more than the surgical intervention. The advantages are more. The long-term followup data is very-very favorable. I think it is a very-very informative interaction both with Dr. P. P. Mohanan and Dr. Anand Khanna. I am really grateful to both of you for your words of wisdom and I am sure in the years to come we will have more data to suggest the role of newer oral anticoagulants in our clinical setting and we will have more publications and more papers, and as Dr. Mohanan mentioned that we need to have more Apps. Similarly, I am sure Dr. Khanna you are also going to create lot App education for aortic dissection, aortic aneurysm as well as peripheral vascular disease. What is the final word from your point of view?


Dr. NN Khanna

That is right. The peripheral vascular disease actually kills 40% of the patients who have coronary artery disease. You may have a good intervention, you have three coronaries you may not die, but if you lose or miss out on diagnosing coexisting peripheral vascular disease, there is a 40% chance you will die of a stroke or renal failure or acute and chronic critical limb ischemia. And also one has to understand there is a very strong correlation between coronary artery disease and erectile dysfunction because the same atherosclerosis of the pudendal artery or the penile artery. So patients who have coronary artery disease, at least 50% of them would have a coexisting block in the 2100 pudendal arteries and they would present with impotence, although they do not talk about it or they do not know about it. This has been proved in the Pen-Appy trial. On the reverse, if you have erectile dysfunction, you predate coronary artery disease by five years so you are the most high risk patient if you have erectile dysfunction you must start looking for coronary arteries because the heart attack is going to come after five years. So either ways it is very closely linked.


Dr. HK Chopra

I think it is very important note Dr. Khanna has mentioned because we do not need only continuing medical education to create an App, but also public health education is very important because most of times erectile dysfunction takes place people are hesitant to discuss about it. It is very devastating and very demoralizing. I think it is very important we must create many Apps on different aspects of peripheral vascular disease and aortic disease to disseminate information and knowledge. You are an ocean of peripheral vascular disease and you have so much of experience in Asia. I think you should create lot of Apps from India, which world should follow and I am sure Dr. Mohanan is going to create special Apps in atrial fibrillation and create the guidelines of India for the world to follow. My personal philosophy is, we should not look at the West all the time. The West should look at the East. Thank you very much for being with us.


Dr. NN Khanna

Thank you.


Tags
  • Heart Attack
  • MI
  • ECG
  • Hypertension
  • Bypass Surgery
  • Stent
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