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Date: 25-04-2013 Newer Beta Blockers in Hypertension

By Dr. Nakul Sinha, Lucknow

I have been asked to speak on newer beta blockers in hypertension.  With due permission, I have also included some slides for heart failure, because I think that’s a gradual extension or an unavoidable thing that most of the physicians cardiologist are going to see in their practice.


I think Dr. Ram made a very good point when he said that we need to have a meeting where you get the encyclopedic knowledge because this is what exactly happens with the drugs that we know little of them and we use much more.  These meetings are just right platform where we try to clear our doubts, where we have specific questions, and at least attempts are made to give specific answers based on whatever latest knowledge that we have.  Knowledge is obviously ever-changing and tomorrow I may be wiser than what I am today.  So, lets always remember that we should be questioning ourselves, our prescriptions, our knowledge, and our attitudes constantly to keep on trying and improve.  This is just predicting that this how perhaps knowledge is also being dissipated amongst the medical professional.  Something like the breaking news or something that you are shown folders that this is a new drug arrival, this is what happens, and this is what it does, but what is important is that we should read up, dissect out, understand and only then start using it in our patients in whatever specific indications that we think that the particular drug is going to be helpful.


Beta blocker is obviously something which cannot be covered; you may go on debating for days and weeks, so I will just be touching upon a few things.  I am thankful to the previous speakers for having taken up much of things and I will skip through those slides.


As with calcium channel blockers perhaps beta blockers also have so many facets to them that the choice and use and dosage and the particular clinical situation for any beta blocker is extremely important.  Especially with the "doubts" being raised about some of the beta blockers not only in some specific instances, but in the long term management and outcomes of patients.  Any choice obviously of any drug is going to be regulated by these side effects, metabolic effects, efficacy and everything has to be nicely balanced.  We know beta blockers are perhaps one of the oldest drugs and in fact when we were at the medical schools, there were hardly any calcium blockers.  Only we heard of verapamil and beta blockers were the only drugs to be used in so many variety of indications, but after that we had selective beta blockers, especially atenolol and metoprolol, and then non-selective vasodilating drugs, which had also some alpha blockade properties as exemplified by labetalol and carvedilol, although they are slightly different in their use, and in the last 6 or 7 years we have sort of re-discovered another beta blocker which has a selective vasodilating.  The mechanism of vasodilation here is different, not alpha blockade and this is nebivolol.  Beta blockers certainly because of their principal mode of action have so many side effects and the efforts has always been to try and reduce the side effects and try and increase the efficacy.  Initially also although beta blockers were right from start touted as one of the wonder drugs for coronary artery and ischemic heart disease, there was some reluctance to use them post MI till the BHAT trial came where the propranolol was post MI and then there were lots and lots of trials.  Still there is some inhibition because if you have an MI and if you have a heart failure or hypotension whether to use beta blockers or not, what about diabetes, what about extreme old age, co-existing COPD, etc., etc, but please remember beta blockers by any means, by any guidelines are eminently indicated for acute myocardial infarction or post MI patients unless they are contraindicated, and I would perhaps make emphasis that unless they are extremely contraindicated.  For example, many persons may not use in post inferior MI if there is a first degree AV block.  I find that is rather taking caution to the extreme, mostly nothing happens.  Many times you see patients with left bundle branch block, cardiomyopathy, and beta blockers are not being used because of the thinking that they may lead to complete heart block.  Well, its rare, I don’t say that it can never happen, but wherein there is a patient where you are denying the benefit of beta blockers.  Anyway, I won't go into the details, sufficient to say that meta-analysis of so many large trials has shown marked benefits especially in terms of the ultimate outcome, i.e, mortality.


Mostly what we find is that for this use second-generation beta blockers like atenolol and metoprolol are being used.  No doubt they have the largest body of clinical data, long-term followup data, especially for heart failure.  In this section, perhaps metoprolol has much more data and much more reliability in terms of its clinical usage and there have issues raised about the less effectiveness or non effectiveness of atenolol.  Again, perhaps due to paucity of time we will not go too deep into that.


We all know, JNC 7 recommended that the way to tackle hypertension was to see whether there was some compelling indication of one of the 7 classes of drugs that were found to be practically equal in terms of their antihypertensive efficacy and if there was not a compelling indication then you could use perhaps anything you want and then go to the goal blood pressure either with a single drug or a combination of drugs and these were the common compelling indications.  I am sure there is going be some rethinking in JNC 8 that is quite eagerly awaited.  The only thing I see is that it is being awaited and awaited for such a long time, it doesn’t seem to be making its appearance.


The blood pressure reduction mechanism.  In fact this has been sort of written by Dr. Ram that the mechanism of traditional versus the third generation beta blockers, the one which have vasodilatation as a positive effect is slightly different because the third generation beta blockers like carvedilol, nebivolol decrease BP largely through reducing the systemic vascular resistance while still maintaining the cardiac output.  So, therein you may have a qualitative difference which may be turned to the advantage of the clinical situation.  Central aortic blood pressure reduction, I think there was a lot of hue and cry about its importance.  I am not really aware as to how much clinically important it is because it is sort of derived value, but definitely there is some difference, there is some applied importance which can be had by calculating the central aortic pressure reduction and it is thought to be more closely related to some of outcomes in cases of hypertension in the natural history and it is also thought that these newer generation beta blocker have perhaps a better effect and a greater capacity to reduce the central aortic blood pressure.


The third generation beta blockers, no doubt carvedilol has been the most extensively studied and that too mostly in heart failure, also in hypertension, but mostly in heart failure and, I mean, we are all quite well aware of the selective beta blocking properties and alpha blocking properties along with vasodilatation.  Heart failure again is one area where many of the physicians are still sort of prescribing beta blockers, but perhaps in a very small dose.  They are not aggressively building up the dose and many a times you find patients of cardiomyopathy severely reduced ejection fraction and they are still continuing on a very low dose beta blocker for years and years altogether.  Perhaps it looks nice, technically you are right, beta blocker is there in the prescription, but then you need to buildup the dose of beta blocker to perhaps the maximally tolerated or the maximally recommended dose to give the patient full amount of benefit, and the benefit is no doubt absolutely the reduction in mortality.  So, that's a very very great and hard point benefit.


There are many mechanism by which beta blockers are beneficial in heart failure.  I will not try to detail out every one of them, but again please concentrate on the last line that outcome benefit is related to using the target drug dosages from clinical trials and outcome is not as much related to the amount of heart rate reduction.  All the guidelines world over, be it the European or the American, give it a class I indication for beta blockers in heart failure with systolic dysfunction, be it due to post MI or be it due to nonischemic cardiomyopathy, and they should be continued life time unless there is a complication or a contraindication


Here, metoprolol, bisoprolol, and carvedilol these are only 3 beta blocker, one being second generation and the other being third generation, which have been studied in heart failure.  Unfortunately, robust data is not available with any other beta blocker.  There is again no point in trying to list all the data even, I am making a very very short summary of it, but carvedilol has been shown to increase the event free survival, survival without hospitalization also in heart failure, and also been shown to improve left ventricular function, left ventricular ejection fraction by increasing the dosages.  Additionally, it is perhaps the only drug which has been shown to be effective when used in class III or class IV heart failure.  There were many studies obviously, the COMET, the COPERNICUS, it was tried against metoprolol, tried as a solitary drug.  The CAPRICORN trial was a post infarct survival trial for patients with severe LV dysfunction after having a myocardial infarction.  So, all these studies showed a very robust, showed a very dramatic reduction in the mortality, the hardest endpoint that we can ever have, and all these, I mean, be it bisoprolol or carvedilol or even metoprolol in MERIT-HF had a very pronounced benefit.  So, I think that thing should be stressed again and again that unless absolutely contraindicated beta blockers should definitely be used and they should be built up in dosages to the recommended dose or the maximally tolerated dose.


If we take the third generation beta blocker, carvedilol, there is supposed to have some benefit vis-à-vis other beta blockers used in heart failure.  Statistically, yes, there are some figures which say that there is a statistically increased chance of more survival if you use these drugs, although all the trials were not sort of uniformly saying that.   But yes, we can say that overall there is definitely a trend that vasolidalatory beta blockers have a greater effect on overall mortality compared with the nonvasodilating agents. However, if we stick our interpretation to the data on post MI or ischemic ordinary patients then I think metoprolol succinate, the long acting metoprolol, has a better data and a better outcome vis-à-vis carvedilol.  So, I think if it is a confirmed myocardial infarction or a coronary artery disease patient then perhaps we will not be wrong in saying that metoprolol perhaps is still the drug of choice if there is LV dysfunction.


If we have very severe heart failure, ejection fraction less than 20% or 25%, then, perhaps all the drugs CIBIS II, bisoprolol; MERIT heart failure, metoprolol succinate; or  COPERNICUS, carvedilol, they had definite benefit.  So, most of them are very beneficial.  Again, very very minor differences, but may be carvedilol and metoprolol had slightly more benefit.


Right dose, now here is the crux.  There is a significant inverse relationship between the beta blocker dose which is used and the endpoint, i.e., all-cause mortality.  So, if you use a higher dose of beta-blocker the mortality is going to be less and you can go up to, although, its not usually common, 50 mg per day carvedilol or equivalent beta blockade for achieving this benefit.  Now, this mortality affect is not directly proportional to the heart rate reduction.  You may have the same mortality benefit if the heart rate is somewhere here or here, but the mortality benefit may be there, but you need to have a high dose of beta blocker.  So it is not only the heart rate reducing effect, but so many other effects, which also contribute to this beneficial effect.  Now, obviously we should also keep on learning about new things.  Dr. Ram told us very nicely about the basic advantages, perceived advantages of the new calcium blocker and how it is perhaps going to be more promising and should be tried in a greater variety of patients.  Similarly, with this new beta blocker, it has been there around for 7 or 8 years, so it is quite like all the other beta blocker except that there is a nitric oxide induced vasodilating property and it is also been shown to improve diastolic dysfunction.


This is the mechanism by which the actions are there on the heart and on the peripheral blood vessels.  The 3 indications obviously as with any other beta blocker remain coronary artery disease, systemic hypertension, and heart failure.  There has been one study carried out in heart failure, although I confess I am not aware of too many details about it, but that showed a significant reduction in the all-cause mortality.  Mainly the data for this beta blocker has been there in hypertension in different patient groups and uniformly it has been shown, even when compared with other beta blockers or with other potent antihypertensives like ACE inhibitors or ARBs, that the percentage of patients achieving the target blood pressure is never less, it is perhaps same or slightly more when you use this new beta blocker.  It has also been shown to reduce ischemia.  Some treadmill studies are there, symptomatic ischemia definitely, but I would still say that it may not be still prudent to use it as first line antiischemic drug.  It has a high selectivity of beta 1 versus beta 2 therefore the least chances of beta 2 side effects like bronchospasm or insulin sensitivity.  So nebivolol has highest selectivity for the beta 1 adrenergic receptors and that is why there is least adverse effect on airway reactivity and insulin sensitivity.


In some basic studies, antioxidant properties have also been shown but they have also been shown with carvedilol in many other studies.  You may say, based on this publication at least that nebivolol appears to be having more antioxidant properties.  Insulin sensitivity, we are very clear that because of their selectivity for receptors, nebivolol and carvedilol have the least effect on insulin sensitivity or perhaps can benefit that.


Publication after publication have stressed upon the fact that this beta blocker has perhaps the best chance of maintaining or reversing the endothelial dysfunction, which as all of us know is a precursor not only to vascular disease but to hypertension.  All this show that endothelial dysfunction even when we measure a noninvasively by the brachial artery vasodilatory test, nebivolol can perhaps be giving a better result and conversely it may be offering more protection.  This is again shown when compared to atenolol that the blood pressure response was much better compared with atenolol and obviously you have other outlined benefits.  Platelet aggregation, well yes, it has also some antiplatelet activities and maybe it may turn out to be better also on this count in later studies.  Diastolic heart failure, yes nebivolol has also been shown to be beneficial but this is one area where we are not exactly very clear as to what exactly is going to benefit a particular patient of diastolic heart failure.  So, still at least some studies show that this improves the diastolic dysfunction parameters better than other beta blockers, specifically atenolol.  Antihypertensive efficacy, well, it is equivalent to carvedilol and also perhaps to atenolol, but yes we need to have separate dosages for them and it is at least as effective for lowering the blood pressure in mild to moderate hypertensives, and obviously as the trend is we need to have combination therapy, and they will hardly be very few patients having 1 antihypertensive.  So, I think that is a fact of life that we have to accept.


Again, there is a study which is showing benefits in very early hypertension in aortic elastic properties when carvedilol and nebivolol are compared.  Now, these are all very basic studies which are measured first in animal and then usually these are animal data, but then nebivolol was found to be equivalent or slightly superior to carvedilol in not only reducing the heart rate but in improving the diastolic function.


As has been pointed out by previous speakers also this is known side effects of beta blockers:  Depression, fatigue, sexual dysfunction and mostly what happens is that these subtle signs or subtle complaints, either the patients do not discuss or we don’t have the time in our clinics to get to the bottom of their problems and find out whether they are suffering from these psychosomatic effects of beta blockers, but definitely in large well conducted studies these have been shown to be not uncommon side effects.


Here there is one study, although quite some time back which compared atenolol plus chlorthalidone plus a diuretic along with plain atenolol and nebivolol and found nebivolol to be least likely to be causing these side effects.  So, as I said, beta blockers are a very very diversely acting group of drugs and it will be very difficult to pinpoint and say that this patient, this situation requires this particular action and that is why you use this, but as a class they are very good, very well studied, very well documented.  Lakhs and lakhs of patients have been followed up on beta blockers, not only of hypertension or coronary artery disease, but also of heart failure and we know there are so different diverse mechanisms which are likely to benefit the patients and there are some additional benefits also in terms of reduced risk of arrhythmias, membrane stabilizing activity, and their benefits have been seen across all the patient; equal benefit in females, different races, diabetics, elderly etc.  You name a group and beta blockers can benefit them.  So, perhaps the mandate should be to not only know about each and every type of beta blocker that we are likely to use, but to also realize that yes there are some differences and these differences are not small, some very basic differences in different groups of beta blockers and where exactly, which patient subgroup is going to benefit from a particular type that we should try and be clear in our mind.

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