THE BEST PAINKILLER ( NSAID ) IF YOU ALSO HAVE HEART TROUBLE.

The controversy over painkillers for joint pains ( the NSAID or non-steroidal anti-inflammatory drugs ) and heart disease has been raging for quite awhile, I think since the early two thousands. The most popular episode was when MSD had to withdrawal VIOXX from the shelves when there were reports that VIOXX use maybe associated with an increase incidence of heart attacks and anginas. That cost MSD. Actually VIOXX and other similar drugs belong to a group of drugs called the Cox2 inhibitors, which were NSAID like without the gastric toxicity. Actaully the clinical papers linking Cox2 with heart disease were rather inconclusive, partly due to poor methodology and partly from some degree of manufacturer's cover-up of some relevant information and the incompetence of FDA at that time.
However, a recent paper in circulation, published in the May issue of Circulation, seem to suggest that Naproxen ( trade name, Simplex ) seem to be safe. Dr Ray of Vanderbuilt, Nashville, did a retrospective analysis on 48,000patients who were using painkillers and who also have heart disease, and found that some painkillers were associated with an increase incidence of heart disease, while naproxen was not. Five painkillers were studied. Of the NSAIDs, diclofenac ( locally voltaren and cataflam ) seem to come out worse and of the Cox2, Vioxx was worse then celebrax. One must bear in mind that this is a retrospective study with all its attendant bias.
Be that as it may, if I have joint pains and also heart disease, I will use naproxen, and if my stomach cannot tolerate it I will use celebrax. That to me will be reasonable, until I have more data. And that will be what I will advise my patients too.

BP PILLS FOR ALL. IS IT JUSTIFIED?

In the 19th May 2009 issue of BMJ, Dr Law and wald of London, published a meta-analysis of 147 randomised clinical trials, involving about 958,000 patients. They were trying to find out the benefits of lowering BP and also the effects of the various anti-hypertensive drugs and regimes. Their study essentially found a few interesting conclusions. They found that giving BP control drugs to anyone suspected with hypertension had clinical benefit. All patients with hypertension, given anti-hypertensive medications had a reduction in cardiac events rates and strokes of 46% and 62% respectively. When given in combination ( either ACE-I, Beta blockers, thiazide derivatives, CCB, ARBs ), even at half the usual dose, still confer significant benefits. There goes all the difficult to remember clinical guidelines, with all their complicated charts and figures to remember.
These findings will go in-line with the thinking of some of us who believe that our normal BP should be as low as tolerable, to reduce the incidence of MACCE. It is well known that even at BP levels of 120/80mmHg ( the classical normal ), there is still a 2 fold increase in CV events. Nowadays, ( cost apart ), the new groups of anti-hypertension medications are so safe and side-effects so little, that it is only the fear of medication and the cost of medication that keeps us from routinely taking anti-hypertensive medications especially as we reach 60years of age. However, if you think of the potential benefit, of a greater then 50% reduction in incidence of strokes, the cost of medication may become acceptable.
Back in Asia, and in particular Malaysia, there need to be an intense public patient education program. Most patients are rather adverse to taking medications, unless they really feel that their lives are threatened. taking medication in an attempt to prevent a major catastrophic events do require alot of convincing.
Nonetheless, the findings of Dr Law and wald, gives further weight to the concept of trying to produce a polypill, for cardiovascular prevention. These pills will contain half normal doses of ACE-I or ARB, Beta blockers, CCB, aspirin and probably a statin in various combinations.
Will you take a polypill every morning, when you are 60years and above, in an attempt to reduce your risk of stroke and heart disease, by half? Afterall, stroke is a major catastrophy and something that we must all avoid.

GLUCOSE CONTROL IN DIABETES. THE PENDULUM SWINGS AGAIN

Diabetologist and cardiologist differ in their approach to management of diabetics. This stems from the fact that diabetologists see patients with either no or multiple organ damage, and so use glucose levels as a means of judging effectiveness of diabetic control. They reason simply that insulin/sugar is the cause of the problem and so more insulin or less glucose should improve the problem. Cardiac boys on the other hand see diabetics with end organ ( in this case cardiac ) damage. They are more keen to see how treatment of diabetics can reduce end-organ damage. Lately (the last 5 years ) I see more diabetologist talking about major cardiac and cerebral vascular endpoints. This is good. We are almost singing from the same hymn sheet.
Except that now, when diabetologist try to recouncile glucose level control with end organ damage or effect, they end up with confusing results. And we are talking about large diabetic trials done by reknown workers. As a cardiologist, I watch from the side and try and draw conclusions.
On the one hand, we have the intensive control of glucose do harm people ( lets call them the "nay " people ) who feel that intensive glucose control may cause more deaths ( the ADVANCE Study ), or may make no difference ( the ACCORD and the VADT study ). On the other hand, there is the " yea " group who feels that intensive or good glucose control makes a difference in longterm cardiovascular mortality and morbidity ( UKPDS and PROACTIVE ).
In the recent May 23rd issue of Lancet, Dr Ray of Cambridge, did a meta-analysis ( a cheap way of doing a surrogate clinical trial ) on 33,000 patients with 160,000 patient years of followup, showed that intensive glucose level control, does reduce CV morbidity but not mortality, obviously at odds with ADVANCE. Interesting. But it is important to note that this is a meta-analysis, with all the flaws and shortcomings of a meta-analysis.
Whenever I am face with conflicting clinical data like this, I feel that the answer must lie somewhere in between as the individual patient is complex and we need to individualise therapy. It would appear that in some patients, I guess in those with recent onset diabetes, without end-organ involvement, intensive glucose control ( and here I think that the agents use are important ), may reduce longterm CV morbidity amd maybe mortality. In those patients with longstanding diabetes, with established end-organi damage, intensive glucose control may not reverse the end-organ damage, and intensive glucose control here may push you to the brink of hypoglycemia and its attendant risk.
However, I am only a cardiologist, and so probably will not have the final say in this matter. One thing that we can agree on is that the pendulum is still swinging and obviously more work needs to be done. We only hope that future diabetic work will focus not just on glycemic control but also on patient end-points.

A NEW GENERATION OF DES-THE NEVO STENT

The EuroPcr has just started in Barcelona. This is probably the second largest interventional cardiology meeting in the world, after the TCT. It is held every year at Barcelona ( previously it was held in Paris ). The meeting started on 19th May 2009.
One of the first clinical trials presented at this year's EuroPcr was the NEVO RES-ELUTION 1 study. This is a very interesting study, because it is very much a proof of concept. Years ago, JnJ bought a company which manufactures the Conors costar stent. The Conors stent had a very unusual design in that the stent itself has pits ( wells ) in it, which allowed drugs to be used to fill the well, almost like a stent depot with drugs eluting at programmed intervals, which hopefully will fight restenosis in particular and CAD in general. I remember the early days when we had meetings on this stent platform and we were all postulating how usueful this stent platform was, imagining that we could fill it with aspirin, statins, anti-proliferating drugs, steriods, estrogens, and all kinds of other drugs were being suggested.
At last all was not to be. Conors started a clinical trial with this costar stent platform and filled it with paclitexal, and the trial results were disasterous. JnJ bought over the company, just before the results were announced. And when the results were poor, JnJ pulled costar off the amrket, and has been struggling to keep up with the second generation DES since.
Well, it looks like they have not been complacent. They have now sponsored a study called the Res-Elution 1 study, which uses this conors pit-technology on a new stent platform, a cobalt chromium platform, They call this new stent, the NEVO stent and filled the pits ( wells ) with their own sirolimus ( many of us feel that the limus-line is the way to go ), and an erodable polymer. Of course to show that they are good, and better, they compared the Nevo DES with Taxus liberte ( to many of us, the taxus stent, with paclitexal as the drug, is probably the weakest of the DES that we have around ). So JnJ organised a trial, single arm, non-blinded, of Nevo vs Taxus liberte, on a non-inferiority basis. About 400 patients were studied over six months. Late loss ( our way of measuring tissue regrowth in the DES ) at six months was the primary end-point. It is not difficult to predict that Nevo came out better than Taxus. I wonder what will happen if they had compared it with their own Cypher stent or the latest Xience V stent. Well, no body wants to lose twice, so comparing with Taxus makes marketing sense.
Of course, for us clinicians, it is very much a proof of concept. At least they have proven that thepit technology is no harmful, and may work well, if given the right stent base, and reight compounds. I hesitate to call this the Third Generation as many of us will need to see large scale clinical trials to compare the Nevo stent against other DES, and also using clinical endpoints like MACCE as their primary endpoints. Also a longer duration like 9 months to a year, and if possible two to three years, would even be better.
For the moment, the Nevo stent looks promising, and we await more data. For us old-timers, it is good to know that the second generation DES is being improved and better stents are on the way.

LESSER KNOW CONSEQUENCE OF ATRIAL FIBRILLATION. DEMENTIA.

At a recent Heart Rhythm Society meeting in Boston, researchers from Utah presented a paper on the incidence of Atrial Fibrillation ( AF ) and its association with dementia, and Alzheimers. It has been know for a longtime that atrial fibrillation is associated with chronic micro-embolisation to the brain and that patients with AF often get strokes ( the bigger emboli ) or dementia ( the smaller emboli ). These are all consequences of chronic cerebral ischemia from micro and macro-embolism. But the researchers in Utah, led by Dr Jared Bunch, also found that patients with chronic AF also had an increase ( 130% ) risk of Alzheimer's. This association is a bit more difficult to understand. After all Alzheimer's is not strict a cerebro-vascular disorder. It may also have a genetic, infective and inflammatory component. Does this mean that AF is also an inflammatory disorder? as suggested by some studies which showed that ARBs can prevent AF.
Obviously more work needs be done.
AF is a very common arrhythmia, especially in the older age group and has this nasty compliction of strokes. Treatment with anti-coagulants, like warfarin, has been shown to prevent strokes in patients suffering from AF, but this then bring up the issue of side-effects from anti-coagulation with warfarin.
In fact researchers are working feverishly to use radiofrequency ablation as a means of treating AF with some success. More importantly, they are also working hard to see how to prevent AF. This may indeed prove difficult as AF may have a degenerative component and age is a major determinant. But it is also true that healthy cardiac lifestyle, including the prevention and treatment of hypertension, prevention and treatment of diabetes, can also prevent heart disease and AF. I would suggest that we major in this and try to avoid heart disease in our fight against AF and strokes.

ANTI-PLATELET AGENTS ; THE NEW AND THE OLD

When I was training in UK in 1977 ( guess my age then ) one of my consultant hematologist in Glasgow Royal Infirmary, UK,one day informed us that he was travelling to USA, to present a paper at the American cardiology meeting. Being a bit blur then ( those were my younger days ), I never asked which society or which meeting. Also an Asian with a UK consultant at that time, you listen and don't ask too many questions. Anyway, that was also when I learned that cardiology is closely related to hematology, through a process called " atherothrombosis " , basically the cause of all our acute coronary events. From henceford, cardiologist must also understand a fair bit of hematology, especially those parts that has to do with coagulation and blood clotting. In fact, I often joke with our hematologist that cardiologist know more about anti-platelets then the hematologist. When the early aspirin studies first came out, to show that aspirin prevents heart attacks, it was also in many ways a proof of concept. Those early, very elegant work done by Dr M Davis, really make the point very clearly that rupture plagues are obviously a danger to all of us and the cause of many cardiac deaths, and aspirin can prevent that.
We then went thru a phase of developing alternatives as aspirin has this nasty side effects of gastrotoxicity. Ticlopidine, working as a ADP receptor blocker was good. Better than aspirin in terms of efficacy but had the bad side effects of leucopenia, which could kill. I had two female patients ( both post coronary stenting ) who died of leucopenia following the use of ticlid.
Clopidogrel is obviously a very potent anti-platelet agent, also working via the ADP pathway. It is effective and we still use alot of it, especially post DES implantation. We now also realise that Clopidogrel, good as it is does suffer from a few drawbacks, like platelet resistance ( which may have a genetic basis ) and also the fact that its effects are non-reversible. Once clopidogrel goes in, it stays for the whole life of the platelet of about 7-10 days. There is of course also the issue of cost, as clopidogrel is RM8 per tablet ( estimate ).
I think the last drawback, cannot be avoided ( we call it progress ).
Last year saw the launch of prasugrel, following the TIMI 38-Triton study. However, prasugrel, powerful as it is comes with the downside of extra bleeding and its action is also non-reversible
There are however, new anti-platelet agents being developed that will be as powerful as prasugrel, with less platelet resistance and also whose effects on the platelet may be reversible. This week saw the preliminary results of two trials, the CHAMPION-PLATFORM and the PLATO trial, featuring the anti-platelet agent IV Cangrelor and the the oral agent Ticagrelor respectively. It would appear that these two agents, work by a different pathway, blocking the P2Y12 pathway, and is reversible. Looks like IV Cangrelor does not work well but the Phase 3 results of Plato ( Oral Ticagrelor ) may be favourable and will be announced at ESC in September.
Looks like all many pharmas are racing to find a replacement for clopidogrel, as cardiologists are very concern about this issue of clopidogrel resistance. It also means that the days of clopidogrel are numbered, even more so with generics now well on our shores.

DES IS SAFE. EVEN MORE PROOF

The interventional cardiology community is really working hard to fight of the ghost of Sept 2006, Barcelona, where they were bashed by reports that DES were killing more than they were helping. Since then , we have seen publications after publications, presentations after presentations at international meetings that DES is safe and much better then bare metal stents.
Well, last week is no exception. It saw the publication of the SCAAR and Horizon-MI re-analysis of their earlier presented data, and this week in J of the American College of Cardiology of the Ontario registry. All showing that DES were better than bare metal stents in a variety of clinical conditions including primary angioplasty for AMI, SVGs, Left Main Stems, etc, etc. DES have proven to be safer and with better longterm outcomes including less target lesion re-vascularisation. It is fair to say that some of the data analysed, were with two year follow-ups and some with 6 years follow-up ( the SCAAR began in 2003 ).
Even on our shores, I hear less enquiries about " Is the medicated stents safe ?" as opposed to three years ago. Our patients have accepted the DES and we still continue to implant a fair amount of DES every week and month. So far so good. Except of course the cost.
Last week, I saw a family who came to enquire on behalf on a ill relative. He had severe triple vessel disease with poor LV, and is now in heart failure with chest pains. The angiogram report seem to support the need for revascularisation. I discussed that he could go for CABG, which would cost about RM 30-40K nowadays, or PCI with 4 DES which would cost about RM 40-50K. So that with DES for 3VD-CAD, the cost of PCI is the same or even a bit more than CABG. The choice may have to be, which is better in terms of short-term risk and long term outcome.
Basically, what I am saying is that DES is here to stay and we will soon see better and better DES. The problem is, cost may go up.

MOST HYPERTENSION DRUGS, EXCEPT ARBs, BETTER THAN NO TREATMENT FOR CHD RISK REDUCTION

The American Society of Hypertension is meeting in San Francisco this week. One of the papers presented was this one by Dr William Elliot from Rush-Chicago. He and his team did a meta-analysis ( nowadays thats the way to go to save R&D money, and also guarantee a favourable outcome ) of the many hypertension trials after JNC 7. The meta-analysis included 276,000 patients who had hypertension as an entry criteria, and as long as they were on treatment, be it diuretic, beta-blockers, ACE-I or CCB, they did better then those not on treatment or those on placebo. Interestingly, the analysis on those who were hypertensives and taking ARBs ( the new kid on the block ) when compared against placebo, showed no advantage. Meaning that ARBs for hypertension, did not seem to protect the ptients against CV events ( surprisingly ). The authors explained that this may be because, the trials on ARBs included in their analysis, were smaller ARB trials and so the small number may have cause them to lose their statistical power to show a difference. It must be noted that the large ARB trials that we know ( including ONTARGET, with a patient enrolment of 27,000 , were in people at high risk of CV events in CHD and not strictly for hypertension ).
This finding, that treatment for hypertension with drugs ( whichever you chose, except ARBs ), will protect against cardiac events was also true for strokes. So treatment of hypertension, with whichever drug ( except ARBs ) will reduce stroke.
The gist of this is that treat hypertension. Chose whichever drug you or your doctor wish. Be compliant. You will be protected against CV events and stroke. Of course, the better the BP control ( treat to target ) the more the benefit and protection. In fact, baring side effects, the lower the BP the better, I believe.
TREATING HYPERTENSION, SAVES LIVES.

MANAGEMENT OF HBP. PLAYING WITH NUMBERS. WHAT ABOUT THE PATIENT?

Over the weekend, I help organise and also participate in a CME for physicians and paediatricians, at the Legend Hotel. I had planned sessions including three, for the management of HBP, delivered by 1, a senior consultant cardiologist in an institution, 2. a senior consultant cardiologist in private practice and 3. a nephrologist in another institution. Is was refreshing, to say the least, to hear how HBP was managed in three different practice environment. Some are clearly number driven ( control BP to target ), and some are more practical and down to earth, so as to get compliance and better control. Some are charts, graphs driven ( as to proved evidence bsed medicine ). Even the same studies quoted by the different speakers could be interpreted in so many different ways. No wonder the treatment of HBP is in such a mess. I have often wondered how much this contributed to the poor level of adequate control ( 6-8% of all HBP diagnosed ) that exist in our community. It is amazing how we cannot get together for the greater good and agree on simple strategies, so that we can get out cler messages and perhaps this will enhance the level of adequate control.
I would like to think, that just one approach will never be possible because the patients are varied and they have individual factors in their HBP control their mandates one approach over another or one prefered drug over another. I am also certain that the pharmas will not like just one, or even two strategies as some may lose out.
However, over the weekend, I think that we can agree that in patients with HBP, lifestyle modification including losing weight and eating less salt, is important. We must always risk startify our patients, and look for target organ damage, or the lack of target organ damage. Drugs are obviously important. Often, one may need two or even three drugs for adequate control. That of course will bring up the issue of cost and compliance.
In this regard, it is worth nothing that we should see the advent of more pharmas bring in combo pills, in an attempt to lower drug cost and also to help increase complaince. Novartis, when they launch Exforge and when Exforge, receive FDA approval as a second line drug for the management of HBP, made plenty of money. Exforge was very succesful. Now Novartis has just receive FDA approval for another combo pill for HBP, which will essentially be Exforge + a diuretic ( or you can also call it Co-Diovan + CCB ).
I also know ( I have been asked their value ) that many other companies will be doing the same ( bring out more combo pills for HBP ). There should be more ACE-I + CCB combinations coming soon and also ARB + CCB combination.
All these will be good as I hope that it will lower cost, increase complaince and so improve on the number of HBP that will be treated to target.
I also wish to emphasize that although numbers ( levels of control ) are important, treating to lessen and reverse target organ damage and also reducing MACCE ( major adverse cerebral and cardiovascular events ) is even more important. At the end of the day, for all clinicians, it is the patient and what happens to him after 5-10years that is important, and not just numbers.

UPDATE ON HRH SULTAN SELANGOR

We are glad that HRH, the Sultan of Selangor is recovering from a successful operation ( according to Malaysian insider ). As expected, he had a mitral valve repair done by Dr Craig Miller, a very senior cardiac surgeon, one of the best.

THE BIG "SWINE FLU" . SWINDLE. WHAT PANDEMIC?

This issue is really not cardiology, but is of public concern.
To me, this so-called swine flu/Mexican flu/Flu A, it is looking more like another of those American / WHO ( US compliant) and ?UK scam. Yes, there are a few cases of "flu" in Mexico, just as there are a few cases of flu here. Every year, during winter and spring, deaths from "flu " are common and in the USA, hundreds die from "flu". There were 7 H1N1 confirmed deaths in Mexico, 1 in USA ( a Mexican ). Does this sound like a potential epidermic ( let alone pandemic ) to you?? BTW, the association to swine has not yet been worked out. They suspected that. I dare say that the record keeping in Mexico is so bad that we will never know. Now we have the whole world on alert. Airports are checking for "swine flu". How are they going to differentiate ordinary flu ( that all of us get every now and then ) from Swine flu? Does it mean that anyone with fever on a flight and who ( unfortunately ) had some link with Mexico, has swine flu? Can you see how scientific is that? By the time the virus is identified, it will be 2 weeks. In the meantime, the unfortunate "victim" is quarantined, and isolated. Can you see the price that common people have to pay?, because of the scare by the Americans? Let me assure you that the H1N1 virus, if it is really that one, is the common base for many virus, and you cannot differentiate the signs and symptoms caused by this virus from the rest. So the association in someway with Mexico, is what makes them say "Swine flu", eg a Mexican on your flight, you shook hands with a Mexican, you stayed in a hotel with someone who was from Mexico, etc. etc.etc. How scientific?
Why then did the ugly American do this? Looks like it may have to do with their pharma and their high level connections. It is wellknown that powerful politicians in USA with shares in large pharmas, and in the company that makes "tamiflu"the flu vaccine, ( which by the way helps little ) has something to do with this. Remember, when the swine flu was announced last week, the Dow Jones went down, but the pharma stocks when up. The US pharmas are making millions when common folks in countries where the economy is trying to recover, is being quarantined, cant get to work. The countries trying to recover spend more money on a scare/scam. The economy will then take longer to recover. Learn how you can trick the world and reap profits if you are strong and powerful, when you can influence the media, and even twist the arm of WHO. If this is not a swindle and a scam, what else is. I am disappointed with mr Obama. He has been misled by his advisers.
Oh, the common measures to be more healthy and adopt hygeinic techniques,is correct and proper. We should all be careful, wash our hands, keep good hygeine, do not share handkechief, drink plenty of water, get enough rest, etc., etc., all that is good for us for all time. But there is no epidermic, no pandermic.
7 confirmed H1N1 deaths in Mexico ( the index country ), a hundred plus cases in Mexico, a few tens of cases in USA, Canada, a few here and there, Does it sound like a pandermic to you. Every year flu season probably has more cases and deaths than these.
I wish that the Malaysian Government will see through all these underhanded American tricks and not waste too much money. Promote general hygeine and be on the alert, for all unusual illness would be a good thing.
Swine flu, what swine flu? Pandermic, what pandermic. Another American / WHO / BBC-UK scam and swindle.