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Are Probiotics A Panacea Or Pure Hype?: The Gullible Gastroenterologist Weighs In

Please allow me to introduce myself.  I am the Gullible Gastroenterologist.  I’ve been around for a long long year, and today I have been given the opportunity by my good friend, the Skeptical Cardiologist (SC), to guest-blog on issues involving the GI tract.

As opposed to my skeptical friend, I had been very trusting by nature. But the SC has opened my eyes to the importance of fact-based medicine.  Seems to be a pretty good way to treat patients while making informed decisions based on the facts.

When the SC approached me to comment about probiotics, I jumped at the chance.  What could possibly be easier than discussing the obviously positive effects associated with ingesting good bacteria?  I mean, it says “good” right there in the description!  But then I remembered the SC’s insistence on giving weight to the facts.  And that’s when things started to get a more problematic.

What Are Probiotics?

Probiotics are defined by the World Health Organization as “live microorganisms that when administered in adequate amounts confer a health benefit on the host.”  The hope is that these ingested microorganisms will somehow affect the bacterial environment (the flora or microbiota) that already exists in our digestive tract.  This sounds great in theory, but it is important to realize that this issue is far from straight forward.

Go look in the mirror right now.  No seriously.  Do it.  I’ll wait.  I’m going to guess that you saw a human being in front of you (I hope).  Think about all the cells that made up what you saw.  All the cells in all the tissues that make up you.  It has been estimated that the total number of cells in an average 70 kg male equals 3.0 x 1013.  Now we know that bacteria normally reside in our body, but how many?  This has actually been estimated to equal approximately 3.8 x 1013 cells.  So you are made up of MORE bacterial cells than “you” cells.  Think about that for a second.  These bacterial cells are an intrinsic part of us.  Some have even gone so far as to call our gut flora a separate organ or even, when combined with our immune system, another sense akin to sight, smell, or touch.

So it is clear that the gut flora should be looked upon with respect, and we have known this for some time.  When animals are raised within isolators to create germ-free animals, we can see evidence that the gut microbiota influences normal neurological development and cognition, digestion, immune response, growth, and metabolism.  So somehow changing the gut microbiota might be effective in treating disease or alleviating certain symptoms, right?  Well, that is the idea behind many sources which claim that probiotics boost immune response, improve the health of your digestive tract, relieve dermatological conditions, cure or prevent autism, treat erectile dysfunction, and so on.

But there is a huge gap between the actual science of attempting to alter the gut microbiome and these unsupported ever-growing claims.  The main issue is that the gut microbiome is extremely complicated.  There is great individual variability between the types and concentrations of bacteria that live in my gut, and those that live in your gut.  Even the Great SC has his own unique concoction of gut flora.  In fact researchers have shown that the DNA makeup of the bacteria in an individual’s intestine is like a fingerprint and is remarkably stable in each individual.  Even after a year, these researchers were able to identify participants in their study just from the analysis of their unique gut flora.

So if we all have our unique gut flora, how can we determine what strains of bacteria to use to treat a patient for whatever ailment we are trying to cure?  What dosage or concentration should we use?  By what route should we introduce our special concoction?  Maybe more importantly, is any of this safe for us?  Can probiotics actually do us harm?

This becomes even more problematic due to the under regulation of the sources of these probiotics.  When we obtain these probiotics from various sources, it’s hard to know exactly what is in these products.  Multiple studies have found discrepancies between what we see on the label and what is actually in the bottle.  In 2015, an analysis of 16 probiotic products found that only one of them matched the bacterial species reported on the label.  Furthermore, if we are trying to somehow alter our bacteria microbiota, we would optimally want live bacteria in the product, and we know that this is not always the case.

Gastrointestinal Benefits Of Probiotics

So from a gastrointestinal perspective, what are the scientifically proven health benefits of probiotics?  These appear to be few and far between.  The majority of the studies have failed to reveal any benefits in individuals that are already healthy.  There seems to be no evidence that people with normal gastrointestinal tracts benefits from these products.

What about folks that are not healthy?  Can probiotics cure a gastrointestinal disease or a condition?  

Many people with irritable bowel syndrome (IBS) come to see the Gullible Gastroenterologist every day.  Although some individual studies have shown some positive effect from probiotics on the symptoms that can be associated with IBS, there is not enough data to recommend any particular strain of bacteria for this condition, and these studies are even more problematic given that even the placebo rate for treatment of IBS averages approximately 40%.

For patients with ulcerative colitis, a disease that causes abnormal inflammation in the large intestine, some small studies have suggested some potential benefits, but combining the results of these studies together does not prove any reliable benefit.

There has been no proven benefit regarding the use of probiotics in Crohn’s disease, a condition similar to ulcerative colitis that can affect anywhere in the gastrointestinal tract.

Small controlled studies do suggest that a probiotic preparation called VSL#3 can be effective in a condition called Pouchitis.  This is a specific condition that can affect patients with ulcerative colitis that have undergone a certain surgery to treat the disease.

There is no evidence to suggest that probiotics are effective in treating celiac disease.

Probiotics And C. difficile Infection

And now we get to the intriguing topic of Clostridium difficile associated colitis.  Clostridium difficile infection typically occurs in patients who have received antibiotics for therapy for bacterial infections elsewhere in the body, pneumonia for example.  The antibiotics can alter the bacterial flora of the gut leading to overgrowth of the C. difficile bacteria.  This overgrowth leads to production of a toxin and subsequent inflammation of the colon.  This bacteria can form spores and so in some patients this condition can be very difficult to treat, resulting in multiple recurrences. 

One of the treatments for recurrent C. difficile infection involves fecal transplantation: transferring stool from a healthy patient to the affected individual. 

The Gullible Gastroenterologist had the opportunity to participate in a fecal transplantation procedure.  The stool from a related donor was prepared in a blender by an infectious disease specialist colleague of mine (this is the reason I absolutely do not attend cocktail parties hosted by that particular physician).  I performed a colonoscopy on the patient and the stool mixture was instilled into the patient’s colon. 

The patient did well with no recurrences, and fecal transplant does appear to be a promising tool in the armamentarium in treatment of recurring C. difficile infection.  That being said, there is insufficient data to support routine use of probiotics for prevention of C. difficile colitis or for treatment of active C. difficile colitis.

Why Are Probiotics Ineffective?

So there is little convincing evidence that probiotics positively effect gastrointestinal disorders.  One reason might be that bacteria from a probiotic supplement might not actually succeed in colonizing the human intestinal tract.  A recent study concluded that in some patients, probiotic strains could be identified in samples obtained from some study participants, but in others, those probiotic strains were undetectable. 

In another study, researchers looked at the fecal microbiome in patients that had received antibiotics.  Normally, a person’s microbiome will recover on its own over time after receiving antibiotics.  This usually takes about 21 days without any intervention.  Surprisingly, administering probiotics to these subjects actually delayed recovery of the microbiome to the pre-antibiotic state to greater than five months.  What does this mean?  Is this good?  Is this bad?  The answer is that we just don’t know.  Yet.

Harm From Probiotics?

Can probiotics do harm?  Although these agents are generally felt to be safe in healthy individuals, we don’t know the long term consequences.  Furthermore, probiotics should be used with caution in patients with chronic disease, are immunocompromised, or are otherwise vulnerable (such as elderly patients).

Bottom Line: More Research Needed Before Usefulness Of Probiotics Proven

So the bottom line?  Research on the fecal microbiome is certainly exciting.  This area of study definitely has the potential to be very important and likely holds the key to discovering the underlying pathophysiology to many conditions. 

But in the year 2019, we just do not have enough information to determine which preparations may be helpful, which patients should be targeted, and how. 

Although I am hopeful that someday probiotics might be an effective tool in treating some of the diseases and conditions that my patients suffer from today, I am just not gullible enough to buy into the hype associated with unsubstantiated claims regarding their usefulness until we learn much much more.

Gullibly yours,

DSL


The Gullible Gastroenterologist,

Dave Lotsoff,  lives south of Delmar in University City, Missouri  and when he’s not singing like Jim Morrison for the skeptical cardiologist’s band he practices gullible clinical gastroenterology  in St. Louis.

-ACP

N.B. Probiotics have also been promoted for lowering blood pressure and reducing risk of cardiovascular disease but the proof of benefit is similar to that for GI problems-severely lacking.

It’s far too early to recommend probiotics  for preventing or treating any chronic diseases.

FDA Recalls More Generic Blood Pressure Meds: Where Are Your Medications Manufactured?

In July of 2018, the FDA made a series of voluntary recalls of several versions of the generic blood pressure medication valsartan which were made in China and were contaminated by the “possible carcinogen,”  N-nitrosodimethylamine (NDMA).

At the time I asked readers the question, “Is your BP med made in china and is it safe?” as it became clear that now in the US users of medications must be very aware of the source and quality of the products they put in their body.

Generic prescription medications and OTC products are highly likely to be manufactured out of the US and with minimal oversight.

Since then the FDA has announced multiple other recalls for companies producing angiotensin II receptor blockers (ARBs) in the same class as valsartan, including products containing losartan and irbesartan,. These drugs have been found to be contaminated contaminated with NDMA or another carcinogen  N-nitrosodiethylamine (NDEA).

The recall now includes irbesartan and losartan plus additional lots of valsartan. Thus, some patients who we switched from valsartan to losartan are now having to switch again.

Click the following links to review updated lists of irbesartan products under recall, losartan medications under recall, valsartan products under recall and valsartan products not under recall.

Here’s  the FDA’s valsartan alert notice from 1/2/19

FDA is alerting patients and health care professionals to Aurobindo Pharma USA’s voluntary recall of two lots of valsartan tablets, 26 lots of amlodipine and valsartan combination tablets, and 52 lots of valsartan and hydrochlorothiazide (HCTZ) combination tablets due to the amount of N-Nitrosodiethylamine (NDEA) in the valsartan active pharmaceutical ingredient. Aurobindo is recalling amlodipine and HCTZ only in combination medications containing valsartan. Neither amlodipine nor HCTZ is currently under recall by itself.

Aurobindo is recalling lots of valsartan-containing medication that tested positive for NDEA above the interim acceptable daily intake level of 0.083 parts per million.

The agency continues to investigate and test all angiotensin II receptor blockers (ARBs) for the presence of NDEA and N-Nitrosodimethylamine (NDMA) and is taking swift action when it identifies these impurities that are above interim acceptable daily intake levels.

FDA also updated the list of valsartan products under recall and the list of valsartan products not under recall.

FDA reminds patients taking any recalled ARB to continue taking their current medicine until their pharmacist provides a replacement or their doctor prescribes a different medication that treats the same condition. Some ARBs contain no NDMA or NDEA.

Fortunately, there are multiple generic  and brand nameARBs we can substitute for the recalled products.

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Patients Discover How Hard It Is To Find Non-Chinese Medications

When I tried to find the source of my generic medications, the results were eye-opening:

 my cholesterol drug is made in India by an Indian company and my blood pressure drug is made in Columbus, Ohio, by a Jordanian company.

I had not realized how globalized the pharmaceutical industry had become.

Many readers also researched the source of the pills they were taking and shared their experience through comments on my blog:

“Frustrated” wrote

My cardiologist changed my blood pressure med to irbesartan. Another generic ARB. I went to get it filled today at a local grocery store pharmacy. I asked where it was made and they showed me the bottle. Guess what? It was SOLCO/Prinston as distributor and Zhejiang Huahai Pharmaceuticals LTD – the same manufacturer as the tainted valsartan. Exactly the same. Despite the recent horrible FDA inspection report of that facility which is posted online here: https://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/CDERFOIAElectronicReadingRoom/UCM621162.pdf

Also, the FDA has found another cancer causing chemical in the drug since I last wrote – now there are two. I checked at [MAJOR CHAIN] pharmacy – they use the SAME CHINESE MANUFACTURER. I checked at [MAJOR CHAIN 2] – yep, they use the SAME CHINESE MANUFACTURER. This is really starting to get scary. I’m trying hard to find a pharmacy that has the non-Chinese version (there are 16 other generic manufacturers of the drug). My insurance company only permits me to use the pharmacies I tried today. Funny how everyone is buying Chinese. Does that validate the claims made in the Epoch article. Is this really that Chinese are undercutting everyone else? I’m just disgusted. I will tell you that if I owned a pharmacy I would not purchase my generics from the same company that just caused one of the largest drug recalls in history. It must be really really cheap. Really really cheap.

Mitch writes:

I have been taking Losartan, but became really concerned with the latest news about carcinogens found in two more BP medications. I called EVERY local pharmacy, including big-box stores, grocery store pharmacies, independent pharmacies, and traditional pharmacies. Not a single one has US-made losartan. Every one of them has stock of meds made in either China or India. One pharmacists told me that he had no control of what he sells; it’s all decided on the corporate level. Another said that he would stock the cheapest generic he could find. Still another pharmacy tried to convince me that Citron, Torrent, and Solco are New Jersey companies selling US-made drugs. It takes only a few minutes of Internet research to prove them wrong. Apparently, there is no incentive to stock US-made drugs. I agree, the consumers have to take action and write to their representatives demanding answers from the FDA.

BIS wrote:

I have just had the same experience. My Indian made Valsartan (Camber) was recalled so my doctor switched me to Irbesartan 150 mg tablets which at my local CVS were also manufactured by Camber. I reluctantly took these while searching for US or European made alternatives. I just went to CVS to get my refill. When I got home instead of the Indian Irbesartan I received a bottle manufactured by Zhejiang Huahai Pharmaceutical Co. Ltd.,(ZHP) Xunqiao, Linhal, Zhejiang China. I am a mechanical engineer not a chemistry major but I believe Irbesartan contains API which is what has been the problem from this company. Looking at the internet I see that the FDA has and import alert for this company. The import alert halts all ZHP-made API and finished drug products using the company’s API from legally entering the United States (https://www.pharmacist.com/article/fda-places-zhejiang-huahai-pharmaceuticals-import-alert). Let’s see- did the Chinese use good API in this batch….I called the CVS and asked for alternatives and was told “good luck”. My doctor said he will work with me if I can find non Chinese or Indian medication. I go out of my way to buy American made goods as I have worked in manufacturing my entire career and have made numerous trips to China and seen what goes on. My Chinese colleagues when they come to the US fill their bags with US made baby formula and vitamins (which probably contain Chinese ingredients). If anyone finds a US or European source of BP medication please post it.

What Can We Do?

One of my readers, Kate, made the following suggestion which made a lot sense:

write to the Senate committee that oversees the FDA. Demand more clarity in labeling of prescription bottles – the country of origin should be CLEAR and CONSPICUOUS – just like that little “Made in China” sticker on the photo above – but on the prescription label itself. Right now only the pharmacist’s supply bottle has the labeling. Write your congressman and to:

U.S. Senate Committee on Health, Education, Labor & Pensions

428 Senate Dirksen Office Building

Washington, DC 20510

I would encourage patients who are taking these recalled ARBS (which are really good blood pressure medications) to check their pill bottles and check with their pharmacists to determine if they have been recalled. If the pharmacist can’t replace your medication with an identical ARB that hasn’t been withdrawn, ask your physician for one of the alternatives listed above.

Find out what country you’re generic drugs in general are made in and let your congressional representatives know you want better FDA oversight of off-shore pharmacuetical manufacturing along with complete transparency with respect to country of origin.

Skeptically Yours,

-ACP

A Heart Healthy Egg Nog Holiday Toast From Dr. and Mrs. Skeptical Cardiologist!

The skeptical cardiologist wrote a post extolling the virtues of egg nog back in 2013.

Today I’m reposting it and wishing all my readers and patients a great Christmas and a fantastic 2019.

IMG_2051-1



It’s Christmas Eve and you are starting to make merry. Time to break out the egg nog? Or should you eschew this fascinating combination of eggs, dairy and (often) alcohol due to concerns about heart disease?

egg

    • Cardiac deaths

increase in frequency

    • in the days around Christmas.

Could this be related to excessive consumption of egg nog?

Egg nog is composed of eggs, cream, milk and booze. All of these ingredients have become associated with increased risk of heart disease in the mind of the public.
Nutritional guidelines advise us to limit egg consumption, especially the yolk, and use low-fat dairy to reduce our risk of heart disease

A close look at the science, however, suggests that egg nog may actually lower your risk of heart disease.

Eggs are high in cholesterol but as I’ve discussed in a previous post, cholesterol in the diet is not a major determinant of cholesterol in the blood and eggs have not been shown to increase heart disease risk.

Full fat dairy contains saturated fat, the fat that nutritional guidelines tell us increases bad cholesterol in the blood and increases risk of heart attacks. But some saturated fats improve your cholesterol profile and organic (grass-fed, see my previous post) milk contains significant amounts of omega-3 fatty acids which are felt to be protective from heart disease.
Milk and dairy products are associated with a lower risk of vascular disease!

Whether you mix rum, brandy, or whisky into your egg nog or you drink a glass of wine on the side you are probably lowering your chances of a heart attack compared to your abstemious relatives. Moderate alcohol consumption of any kind is associated with a lower risk of dying from cardiovascular disease compared to no alcohol consumption.

So, drink your egg nog without guilt this Holiday Season!
You’re actually engaging in heart healthy behavior.

Eggnoggingly Yours,

-ACP

Apple Watch Fails To Notify Patient Of 3 Hour Episode Of Rapid Atrial Fibrillation

Apple claims that its Apple Watch can detect atrial fibrillation (AF) and appropriately notify the wearer when it suspects AF.

This claim comes with many caveats on their website:

Apparently it needs to record 5 instances of irregular heart beat characteristic of atrial fibrillation over at least 65 minutes before making the notification.

This feature utilizes the watch’s optical heart sensors, is available  in Apple Watch Series 1 or later and has nothing to do with the Apple Watch 4 ECG recording capability which I described in detail in my prior post.

Failure To Detect AF

A patient of mine with known persistent AF informed me yesterday that she had gone into AF and remained in it for nearly 3 hours with heart rates over 100 beats per minute and had received no notification. She confirmed the atrial fibrillation with both AW4 recordings and AliveCor Kardia recordings while she was in it.

The watch faithfully recorded sustained heart rates up to 140 BPM but never alerted her of this even though the rate was consistently over her high heart rate trigger of 100 BPM.

The patient had set up the watch appropriately to receive notifications of an irregular rhythm.

Reviewing her tracings from both the AW4 and the Kardia this was easily diagnosed AF with a rapid ventricular response.

What does Apple tell us about the accuracy of the Apple Watch AF notification algorithm? All we know is the unpublished , non peer-reviewed data they themselves collected and presented to the FDA.

From this link on their website Apple says:

In a study of 226 participants aged 22 years or older who had received an AFib notification while wearing Apple Watch and subsequently wore an electrocardiogram (ECG) patch for approximately 1 week, 41.6% (94/226) had AFib detected by ECG patch. During concurrent wear of Apple Watch and an ECG patch, 57/226 participants received an AFib notification. Of those, 78.9% (45/57) showed concordant AFib on the ECG patch and 98.2 % (56/57) showed AFib and other clinically relevant arrhythmias. These results demonstrate that, while in the majority of cases the notification will accurately represent the presence of AFib, in some instances, a notification may indicate the presence of an arrhythmia other than AFib. No serious device adverse effects were observed

This tells us that about 80% of notifications are likely to be Afib whereas 20% will not be Afib. It is unclear what the “other clinically relevant arrhythmias”  might be. If I had to guess I would suspect PVCS or PACS which are usually benign.

If 20% of the estimated 10 million Apple Watch wearers are getting false positive notifications of afib that means 2 million calls to doctor or visits to ERs that are not justified.  This could be a huge waste of resources.

Thus the specificity of the AF notification is 80%. The other important parameter is the sensivitiy. Of the cases of AF that last >65 minutes how many are detected by the app?

Apple doesn’t seem to have any data on that but this obvious case of rapid AF lasting for 3 hours does not give me much confidence in their AF detection algorithms.

They do have a lot of CYA statements indicating you should not rely on this for detection of AF:

It is not intended to provide a notification on every episode of irregular rhythm suggestive of AFib and the absence of a notification is not intended to indicate no disease process is present; rather the feature is intended to opportunistically surface a notification of possible AFib when sufficient data are available for analysis. These data are only captured when the user is still. Along with the user’s risk factors, the feature can be used to supplement the decision for AFib screening. The feature is not intended to replace traditional methods of diagnosis or treatment.

My patient took her iPhone and Apple Watch into her local Apple store to find out why her AF was not detected. She was told by an Apple employee that the Watch does not detect AF but will only notify her if her heart rate is extremely low or high. I had asked her to record what they told her about the problem.

As I’ve written previously (see here) the Apple Watch comes with excessive hype and minimal proof of its accuracy. I’m sure we are going to hear lots of stories about AF being detected by the Watch but we need some published, peer-reviewed data and we need to be very circumspect before embracing it as a reliable AF monitor.

Skeptically Yours,

-ACP

Don’t Stop Taking Your Statin Cholesterol Drug Based On The Latest News Headline

In a previous post the skeptical cardiologist discussed his approach to a typical sixty-something male, Geo,  who was “on the fence” about taking the statin drug his PCP had recommended (see here.)

After acquiring more information on his level of subclinical atherosclerosis (coronary calcium and vascular screening), and discussing the risks and benefits of statins for primary prevention, I wrote about his experience in using my recommended “compromise approach.”

This approach utilizes a low dose of rosuvastatin taken intermittently with the goal of minimizing any statin side effects, but obtaining some of the benefits of statin drugs on cardiovascular risk reduction.

It worked well for Geo; taking 5 mg rosuvastatin three times weekly lowered his LDL-C (bad cholesterol) by 50%, and he had absolutely no side effects when I reported on him 6 months after starting the drug.

However, when I stayed with Geo and his lovely wife, Wendy, over Thanksgiving in their Annapolis, Maryland house, Geo revealed that he had stopped taking his statin.

Like many patients, he was swayed by a news report suggesting an important “new study” that suggested there was no relationship between cholesterol and heart disease, and that statin drugs were dangerous and should be stopped.

At first I thought the story that he had read was the one I reported here which (appropriately) questions the benefit of statins for primary prevention in patients over the age of 75.

However, after a bit of searching, Geo told me the article that caused him to stop taking his statin was a UK Daily Mail one entitled:

‘No evidence’ having high levels of bad cholesterol causes heart disease, claim 17 physicians as they call on doctors to ‘abandon’ statins

The Daily Mail article says at one point

But the new study, based on data of around 1.3 million patients, suggests doling out statins as a main form of treatment for heart disease is of ‘doubtful benefit’.

Is this really a “new study” that contradicts the great body of evidence showing that statin treatment is safe and effective in preventing heart attacks and stroke in those at high risk for cardiovascular events?

In reality, this is an opinion piece published in a questionable journal* without any new research, and it is the opinion of a collection of well-known (approaching notorious) statin denialists, members of a cult-like organization called The International Network of Cholesterol Skeptics.(THINCS).

Larry Husten, who writes highly informed cardiac journalism at Cardiobrief, gives a good summary of their methods in this description of the authors of an editorial attacking the results of the JUPITER trial:

Nevertheless, the association of the authors with a group like THINCS raises some troublesome questions because, in fact, THINCS members don’t just object to one trial (JUPITER), or just one drug (rosuvastatin), or just the use of statins for primary prevention. They raise objections about ALL cholesterol-lowering trials, ALL cholesterol-lowering drugs, and the use of statins in ALL populations. They constantly harp on the dangerous side effects of  statins, and exploit any bit of evidence they can find to launch their attacks, always ignoring the considerable evidence that doesn’t support their views. So the Archives paper on JUPITER is not really part of the scientific process, since the authors have no interest in the give and take of medicine and science. Their only interest is to attack, at any point, and on any basis, anything related to mainstream science about cholesterol.

The lead and corresponding author, Uffe Ravnskov is the founder of THINCS and author of The Cholesterol Myths – Exposing the Fallacy that Saturated Fat and Cholesterol Cause Heart Disease (2000), which is considered the bible of cholesterol contrarianism.

Ravnskov’s book has been severely criticized in Bob Carroll’s The Skeptic’s Dictionary, which outlines the distortions and deceptive techniques found in the cholesterol skeptics’ arguments.

Harriet Hall wrote an excellent analysis of THINCS 10 years ago at Science-Based Medicine and her concluding sentences are still highly relevant:

“to reject the cholesterol connection and statins entirely is to throw the baby out with the bathwater. In my opinion, THINCS is spreading misinformation that could lead patients to refuse treatment that might prolong their life or at least prevent heart attacks and strokes.”

Indeed, if they were able to convince a highly intelligent patient like Geo, with a science background who also had easy access to the advice of a forward thinking cardiologist to stop taking his statins, who knows how many thousands have been convinced to stop their medications.

So my best advice for Geo and all of you taking statins is the following:

  1. Make sure you really need to be on the drug after engaging in shared-decision making with your physician and learning all you can about your personal risk of cardiovascular disease, the benefits of statins for you, and the potential side effects.
  2. Once you’ve made a decision based on good information and physician recommendation, try to ignore the latest headlines or internet stories that imply some new and striking information that impacts your health-most of these are unimportant.

The evidence for the benefit of statins is based on a deep body of scientific work, which will not be changed by any one new study. There is a very strong consensus amongst scientists who are actively working in the field of atherosclerosis, and amongst physicians who are actively caring for patients, that statins are very beneficial and safe. This consensus is similar to the consensus about the value of vaccines.

Science moves incrementally, and new studies inform those with open minds. The studies in this area that have been most significant in the last few years have actually strengthened the concept that drugs which lower LDL-C without causing other issues lower cardiovascular risk (see here on PCSK9 inhibitors and here on ezetimibe.)

Incrementally Yours,

-ACP

N.B. *The Expert Review of Clinical Pharmacology”is an open access journal, many of which are predatory. Article are solicited and the authors pay to have their work published. For the article in question, the Western Vascular Institute payed the fee. It’s not clear that there is any peer-review process involved.

Some authors have suggested predatory journals are “the biggest threat to science since the inquisition”and I am very worried about the explosive growth in these very weak journals which exist solely to make money.

I realize that writing this piece will engender the wrath of many so before you leave comments impugning my integrity let me reiterate that I receive absolutely nothing from BIG PHARMA. In fact, by writing appropriate prescriptions for statin drugs I reduce my income as my compliant patients avoid hospital and office visits and all kinds of procedures for heart attacks and strokes!

Who Deserves To Be A Wikipedia Article?: The Deletion of Dr. Malcolm Kendrick

Scottish primary care physician and author of The Great Cholesterol Con Dr. Macolm Kendrick began his blog post yesterday with these words:

I thought I should tell you that I am about to be deleted from Wikipedia. Someone sent me a message to this effect. It seems that someone from Manchester entitled User:Skeptic from Britain has decided that I am a quack and my presence should be removed from the historical record.

Although I don’t agree with Kendrick’s statin denialism I do find him an informative, entertaining and different voice in the field of atherogenesis and it didn’t seem right that he should be deleted from Wikipedia.

Apparently, articles on Wikipedia can be proposed for deletion and at Wikipedia: Articles for deletion/Malcolm Kendrick there is an ongoing battle between the forces fighting for deletion of kendrick those fighting for maintenance of his Wikipedia entry.

This wikipedia comment is what initiated the deletion proposition:

Malcolm Kendrick is a fringe figure who agues(sic) against the lipid hypothesis. He denies that blood cholesterol levels are responsible for heart disease and in opposition to the medical community advocates a high-fat high-cholesterol diet as healthy. Problem is there is a lack of reliable sources that discuss his ideas. His book The Great Cholesterol Con was not reviewed in any science journals. Kendrick is involved with the International Network of Cholesterol Skeptics, I suggest deleting his article and redirecting his name to that. Skeptic from Britain (talk) 20:29, 2 December 2018 (UTC)

I have no idea what are valid criteria are for a human becoming an article on Wikipedia (in fact I’ve often thought that I should have an article) but none of the “Skeptic from Britain’s” arguments would sway me to delete Kendrick’s article.

Wikipedically Yours,

-ACP

Skeptical Cardiologist Lowers His Cardiovascular Risk By Marrying The Eternal Fiancee’

The skeptical cardiologist shed his skepticism about marriage today and tied the knot with his Eternal Fiancee’.

This decision was not based on the findings of a recent meta-analysis of 34 studies with more than two million participants that found that that compared with married people, those who were unmarried  ( never married, widowed or divorced)  were 42 percent more likely to have some form of cardiovascular disease and 16 percent more likely to have coronary heart disease.

No, I was not influenced by these observational data which show a 43% increase risk of coronary heart disease death and a 55% increased risk of death from stroke.

Headlines like this from Time magazine:

How Marriage Can Actually Protect Your Heart Health

had no bearing on my decision.

This skeptical cardiologist found the perfect woman for his skeptical ways,

And observations that unmarried patients have longer delays in seeking medical help which influences the timing and benefit of invasive cardiac procedures that reduce mortality played no role in this decision.

Neither did the prospect that a spouse would encourage a more healthy lifestyle and better adherence to treatment nor the buffering hypothesis which suggests that informational or emotional resources from a spouse promote adaptive behaviour and may reduce excessive neuroendocrine response to acute or chronic stressor.

Nope. It was pure and unadulterated love.

Blissfully Yours,

-ACP

Has REDUCE-IT Resurrected Fish OIl Supplements (And Saved Amarin)?

The answers are no and yes.

There is still no reason to take over the counter fish oil supplements.

In fact, a study published Saturday found that fish oil supplementation (1 g per day as a fish-oil capsule containing 840 mg of n−3 fatty acids, including 460 mg of eicosapentaenoic acid [EPA] and 380 mg of docosahexaenoic acid [DHA]

did not result in a lower incidence than placebo of the primary end points of major cardiovascular events (a composite of myocardial infarction, stroke, or death from cardiovascular causes) and invasive cancer of any type.

However, another study  published Saturday (REDUCE-IT) and presented at the annual American Heart Association Scientific Sessions to great fanfare found that an ethyl-ester formulation (icosapent ethyl) of eicosapentanoic acid (EPA, one of the two main marine n-3 fish oils)  reduced major cardiovascular events by 25% in comparison to placebo.

When I wrote about Icosapent ethyl (brand name Vascepa) in a previous blog post in 2015 there was no data supporting its use:

A fish oil preparation, VASCEPA,  available only by prescription, was approved by the FDA in 2012.

Like the first prescription fish oil available in the US, Lovaza, VASCEPA is only approved by the FDA for treatment of very high triglycerides(>500 mg/dl).

This is a very small market compared to the millions of individuals taking fish oil thinking that  it is preventing heart disease.

The company that makes Vascepa (Amrin;$AMRN)would also like to have physicians prescribe it to their patients who have mildly or moderatelyelevated triglycerides between 200 and 500 which some estimate as up to 1/3 of the population.

The company has a study that shows that Vascepa lowers triglycerides in patients with such mildly to moderately elevated triglycerides but the FDA did not approve it for that indication.

Given the huge numbers of patients with trigs slightly above normal, before approving an expensive new drug, the FDA thought, it would be nice to know that the drug is actually helping prevent heart attacks and strokes or prolonging life.

After all, we don’t really care about high triglycerides unless they are causing problems and we don’t care about lowering them unless we can show we are reducing the frequency of those problems.

Data do not exist to say that lowering triglycerides in the mild to moderate range  by any drug lowers heart attack risk.

In the past if a company promoted their drug for off-label usage they could be fined by the FDA but Amarin went to court and obtained the right to promote Vascepa to physicians for triglycerides between 200 and 500.

Consequently, you may find your doctor prescribing this drug to you. If you do, I suggest you ask him if he recently had a free lunch or dinner provided by Amarin, has stock in the company (Vascepa is the sole drug made by Amarin and its stock price fluctuates wildly depending on sales and news about Vascepa) or gives talks for Amarin.

If he answers no to all of the above then, hopefully, your triglycerides are over 500.

And although elevated triglycerides confer an elevated CV risk nearly all prior trials evaluating different kinds  of triglyceride-lowering therapies, including extended-release niacin, fibrates, cholesteryl ester transfer protein inhibitors, and omega-3 fatty acids have failed to show reductions in cardiovascular events

REDUCE-IT, Amarin trumpeted widely in September (before the actual data was published)  now provides impressive proof that it prevents cardiovascular disease. Has the skeptical cardiologist changed his mind about fish oil?

Vascepa Is Not Natural Fish Oil

Although Amarin’s marking material states “VASCEPA is obtained naturally from wild deep-water Pacific Ocean fish” the active ingredient is an ethyl ester form of eicosapentoic acid (EPA) which has been industrially processed and distilled and separated out from the other main omega-3 fatty acid in fish oil (DHA or docosohexanoieic acid).

Natural fish oil contains a balance of EPA and DHA combined with triacylglycerols (TAGS).

So even if the REDUCE-IT trial results can be believed they do not support the routine consumption of  over the counter fish oil supplements for prevention of cardiovascular disease.

Does REDUCE-IT  Prove The Benefit of Purified High Dose EPA?

REDUCE-IT was a large (8179 patients) randomized, double-blind placebo controlled trial

Eligible patients had a fasting triglyceride level of 150 to 499 mg per deciliter  and a low-density lipoprotein (LDL) cholesterol level of 41 to 100 mg per deciliter  and had been receiving a stable dose of a statin for at least 4 weeks. In 2013 the protocol was changed and required a triglyceride level>200 mg/dl.

Participants were randomized to icosapent ethyl (2 g twice daily with food [total daily dose, 4 g]) or a placebo that contained mineral oil to mimic the color and consistency of icosapent ethyl and were followed for a median of 4.9 years. A primary end-point event occurred in 17.2% of the patients in the icosapent ethyl group, as compared with 22.0% of the patients in the placebo group.

More importantly, the hard end-points of CV death, nonfatal stroke and heart attack were also significantly lower in the Vascepa arm compared to the “placebo” arm.

These results are almost unbelievably good and they are far better than one would have predicted given only a 17% reduction in triglycerides.

This makes me strongly consider prescribing Vascepa (something I heretofore have never done) to my higher risk patients with triglycerides over 200 after we’ve addressed lifestyle and dietary contributors.

Perhaps the high dose of EPA (4 grams versus the 1 gram utilized in most trials) is beneficial in stabilizing cell membranes, reducing inflammation and thrombotic events as experimental data has suggested.

Lingering Concerns About The Study

Despite these great results I have some concerns:

  1. The placebo contained mineral oil which may not have been neutral in its effects. In fact, the placebo arm had a significant rise in the LDL cholesterol.
  2. Enrolled patients were predominantly male and white. No benefit was seen in women.
  3. Higher rates of serious bleeding were noted in patients taking Vascepa
  4. Atrial fibrillation developed significantly more often in Vascepa patients (3.1%) versus the mineral oil patients (2.1%)

Finally, the trial was sponsored by Amarin Pharma. This is an aggressive company that I don’t trust.  The steering committee consisted of academic physicians (see the Supplementary Appendix), and representatives of the sponsor developed the protocol,  and were responsible for the conduct and oversight of the study, as well as the interpretation of the data. The sponsor was responsible for the collection and management of the data. All the data analyses were performed by the sponsor,

After i wrote my negative piece on Vascepa in 2015 a number of Amarin investors attacked me because Vascepa is the only product Amarin has and any news on the drug dramatically influences its stock price. Here is the price of Amarin stock in the last year.

The dramatic uptick in September corresponds to the company’s announcement of the topline results of REDUCE-IT. Since the actual results have been published and analyzed the stock has dropped 20%.

High Dose Purified and Esterified EPA-Yay or Nay?

I would love to see another trial of high dose EPA that wasn’t totally under the control of Amarin and such trials are in the pipeline.

Until then, I’ll consider prescribing Amarin’s pills to appropriate patients* who can afford it and who appear to have significant residual risk after statin therapy*.

But, I will continue to tell my patients to stop paying money for useless OTC fish oil supplements.

Megaskeptically Yours,-

ACP

N.B.* Appropriate patients will fit the entry criteria for REDUCE-IT described below.

Patients could be enrolled if they were 45 years of age or older and had established cardiovascular disease or were 50 years of age or older and had diabetes mellitus and at least one additional risk factor. Eligible patients had a fasting triglyceride level of 150 to 499 mg per deciliter (1.69 to 5.63 mmol per liter) and a low-density lipoprotein (LDL) cholesterol level of 41 to 100 mg per deciliter (1.06 to 2.59 mmol per liter) and had been receiving a stable dose of a statin for at least 4 weeks;

So either secondary prevention (prior heart attack or stroke) or primary prevention in patients with diabetes and another risk factor.

 

 

Coronary Artery Calcium Scan Embraced By New AHA/ACC Cholesterol Guidelines: Will Insurance Coverage Follow?

The skeptical cardiologist has been utilizing coronary artery calcium (CAC) scans to help decide which patients are at high risk for heart attacks, and sudden cardiac death for the last decade. As I first described in 2014, (see here) those with higher than expected calcium scores warrant more aggressive treatment and those with lower scores less aggrressive treatment.

Although , as I have discussed previously, CAC is not the “mammography of the heart” it is incredibly helpful in sorting out personalized cardiovascular risk. We use standard risk factors like lipids, smoking, age, gender and diabetes to stratify individuals according to their 10 year risk of atherosclerotic cardiovascular disease (ASCVD) but many apparent low risk individuals (often due to inherited familial risk) drop dead from ASCVD and many apparent high risk individuals don’t need statin therapy.

Previously, major guidelines from organizations like the AHA and the ACC did not recommend CAC testing to guide decision-making in this area. Consequently, CMS and major insurers have not covered CAC testing. When my patients get a CAC scan they pay 125$ out of their pocket.. For the affluent and pro-active this is not an obstacle, however those struggling financially often balk at the cost.

I was, therefore, very pleased to read that the newly updated AHA/ACC lipid guidelines (full PDF available here) emphasize the use of CAC for decision-making in intermediate risk patients.

 

 

 

 

 

 

 

 

For those patients aged 40-75 without known ASCVD whose 10 year risk of stroke and heart attack is between 7.5% and 20% (intermediate, see here on using risk estimator) the guidelines recommend “consider measuring CAC”.

If the score is zero, for most consider no statin. If score >100 and/or >75th percentile, statin therapy should be started.

I don’t agree totally with this use of CAC but it is a step forward. For example, how I approach a patient with CAC of 1-99 depends very much on what percentile the patient is at. A score of 10 in a 40 year old indicates marked premature build up of atherosclerotic plaque but in a 70 year old man it indicates they are at much lower risk than predicted by standard risk factors. The first individual we would likely recommend statin therapy and very aggressive lifestyle changes whereas the second man we could discuss  taking off statins.

Neil Stone, MD, one of the authors of the guidelines was quoted  as saying that the imaging technique is “the best tiebreaker we have now” when the risk-benefit balance is uncertain.

“Most should get a statin, but there are people who say, ‘I’ve got to know more, I want to personalize this decision to the point of knowing whether I really, really need it.’ … There are a number of people who want to be certain about where they stand on the risk continuum and that’s how we want to use it,”

Indeed, I’ve written quite a bit about my approach to helping patients “get off the fence” on whether or not to take a statin drug.

I recommend reading “Are you on the fence about taking a statin drug” to understand the details of using CAC in decision-making and the follow up post on a compromise approach to reducing ASCVD risk.

Deriskingly Yours,

-ACP

Full title of these new guidelines includes an alphabet soup of organization acronyms

2018 AHA/ACC/AACVPR/AAPA/ABC/ACPM/ADA/AGS/APhA/ASPC/NLA/PCNA Guideline on the Management of Blood Cholesterol

N.B. For your reading pleasure I’ve copied the section in the new guidelines that discusses in detail coronary artery calcium.

Two interesting sentences which I’ll need to discuss some other time

-When the CAC score is zero, some investigators favor remeasurement of CAC after 5 to 10 years

CAC scans should be ordered by a clinician who is fully versed in the pros and cons of diagnostic radiology.

In MESA (Multi-Ethnic Study of Atherosclerosis), CAC scanning delivered 0.74 to l.27 mSv of radiation, which is similar to the dose of a clinical mammogram 

-4.4.1.4. Coronary Artery Calcium

Substantial advances in estimation of risk with CAC scoring have been made in the past 5 years. One purpose of CAC scoring is to reclassify risk identification of patients who will potentially benefit from statin therapy. This is especially useful when the clinician and patient are uncertain whether to start a statin. Indeed, the most important recent observation has been the finding that a CAC score of zero indicates a low ASCVD risk for the subsequent 10 years (S4.4.1.4-1–S4.4.1.4-8). Thus, measurement of CAC potentially allows a clinician to withhold statin therapy in patients showing zero CAC. There are exceptions. For example, CAC scores of zero in persistent cigarette smokers, patients with diabetes mellitus, those with a strong family history of ASCVD, and possibly chronic inflammatory conditions such as HIV, may still be associated with substantial 10-year risk (S4.4.1.4-9–S4.4.1.4-12). Nevertheless, a sizable portion of middle-aged and older patients have zero CAC, which may allow withholding of statin therapy in those intermediate risk patients who would otherwise have a high enough risk according to the PCE to receive statin therapy (Figure 2). Most patients with CAC scores ≥100 Agatston units have a 10-year risk of ASCVD≥7.5%, a widely accepted threshold for initiation of statin therapy (S4.4.1.4-13). With increasing age, 10- year risk accompanying CAC scores of 1 to 99 rises, usually crossing the 7.5% threshold in later middle age (S4.4.1.4-13). When the CAC score is zero, some investigators favor remeasurement of CAC after 5 to 10 years (S4.4.1.4-14–S4.4.1.4-16). CAC measurement has no utility in patients already treated with statins. Statins are associated with slower progression of overall coronary atherosclerosis volume and reduction of high-risk plaque features, yet statins increase the CAC score (S4.4.1.4-17). A prospective randomized study of CAC scoring showed improved risk factor modification without an increase in downstream medical testing or cost (S4.4.1.4-18). In MESA (Multi-Ethnic Study of Atherosclerosis), CAC scanning delivered 0.74 to l.27 mSv of radiation, which is similar to the dose of a clinical mammogram (S4.4.1.4- 19). CAC scans should be ordered by a clinician who is fully versed in the pros and cons of diagnostic radiology.

Downloaded from http://ahajournals.org by on November 11, 2018

from Grundy SM, et al.
2018 Cholesterol Clinical Practice Guidelines

Why We Need To Replace Hippocrates’ Oath And Apocryphal Trope

The skeptical cardiologist has never liked the Hippocratic Oath and so was quite pleased to read that it is gradually being replaced by more appropriate oaths with many medical graduates taking an excellent pledge created by the World Medical Association.

Here’s the first line of the Hippocratic Oath

Asclepius with his serpent-entwined staff, Archaeological Museum of Epidaurus

I swear by Apollo the Healer, by Asclepius, by Hygieia, by Panacea, and by all the gods and goddesses, making them my witnesses, that I will carry out, according to my ability and judgment, this oath and this indenture.

Much as I enjoy the ribald hi jinx of the gods and goddesses in Greek mythology and appreciate the back story behind words like panacea and hygiene* I just don’t feel it is appropriate to swear an oath to mythical super beings.

Let Food Be Thy Medicine-The Apocryphal Hippocratic Trope

Hippocrates is often cited these days in alternative medicine circles because he is alleged to have said “let food be thy medicine and medicine thy food.”

I’ve come across two articles that are well worth reading on the food=medicine trope which is often used by snake oil salesmen to justify their useless (presumably food-based) supplements.

The first , entitled “Hey, Hippocrates: Food isn’t medicine. It’s just food” comes from  Dylan Mckay, a nutritional biochemist at the Richardson Centre for Functional Foods and Nutraceuticals, He writes:

Food is so much more than medicine. Food is intrinsically related to human social interactions and community. Food is culture, love, and joy. Turning food into medicine robs it of these positive attributes.

A healthy relationship with food is essential to a person’s well-being, but not because it has medicinal properties. Food is not just fuel and it is more than nutrients — and we don’t consume it just to reduce our disease risk.

Seeing food as a medicine can contribute to obsessing about macronutrientintake, to unfairly canonizing or demonizing certain foods, and to turning eating into a joyless and stressful process.

People tend to overvalue the immediate impact of what they eat, thinking that a “super food” can have instant benefits while undervaluing the long-term effects of what they consume over their lifetime.

The Appeal to Antiquity

The second article is from the always excellent David Gorski at Science-based Medicine entitled let-food-be-thy-medicine-and-medicine-be-thy-food-the-fetishism-of-medicinal-foods.

Gorski notes that just because Hippocrates is considered by some to be the “father of medicine” and his ideas are ancient doesn’t make them correct:

one of the best examples out there of the logical fallacy known as the appeal to antiquity; in other words, the claim that if something is ancient and still around it must be correct (or at least there must be something to it worth considering).

Of course, just because an idea is old doesn’t mean it’s good, any more than just because Hippocrates said it means it must be true. Hippocrates was an important figure in the history of medicine because he was among the earliest to assert that diseases were caused by natural processes rather than the gods and because of his emphasis on the careful observation and documentation of patient history and physical findings, which led to the discovery of physical signs associated with diseases of specific organs. However, let’s not also forget that Hippocrates and his followers also believed in humoral theory, the idea that all disease results from an imbalance of the “four humors.” It’s also amusing to note that this quote by Hippocrates is thought to be a misquote, as it is nowhere to be found in the more than 60 texts known as The Hippocratic Corpus (Corpus Hippocraticum).

Gorski goes on to point out that:

this ancient idea that virtually all disease could be treated with diet, however much or little it was embraced by Hippocrates, has become an idée fixe in alternative medicine, so much so that it leads its proponents twist new science (like epigenetics) to try to fit it into a framework where diet rules all, often coupled with the idea that doctors don’t understand or care about nutrition and it’s big pharma that’s preventing the acceptance of dietary interventions. That thinking also permeates popular culture, fitting in very nicely with an equally ancient phenomenon, the moralization of food choices (discussed ably by Dr. Jones a month ago


We’ve learned a lot about medicine and nutrition in the last 3 thousand years. We can thank Hippocrates, perhaps, for the idea that diseases don’t come from the gods but little else.

It’s time to upgrade the physician pledge  and jettison the antiquated Hippocratic Oath.

We now have real, effective medicines that have nothing to do with food for many diseases. It’s important to eat a healthy diet.

But the food=medicine trope is just too often a  marker for pseudo and anti-science humbuggery and should also be left behind.

Hygienically Yours,

-ACP

*From Wikipedia, an explanation of the Gods and Goddesses mentioned in the Hippocratic oath

Asclepius represents the healing aspect of the medical arts; his daughters are Hygieia(“Hygiene”, the goddess/personification of health, cleanliness, and sanitation), Iaso (the goddess of recuperation from illness), Aceso(the goddess of the healing process), Aglæa/Ægle (the goddess of the glow of good health), and Panacea (the goddess of universal remedy).


The Physician’s Pledge

  • Adopted by the 2nd General Assembly of the World Medical Association, Geneva, Switzerland, September 1948
    and amended by the 22nd World Medical Assembly, Sydney, Australia, August 1968
    and the 35th World Medical Assembly, Venice, Italy, October 1983
    and the 46th WMA General Assembly, Stockholm, Sweden, September 1994
    and editorially revised by the 170th WMA Council Session, Divonne-les-Bains, France, May 2005
    and the 173rd WMA Council Session, Divonne-les-Bains, France, May 2006
    and the WMA General Assembly, Chicago, United States, October 2017

  • AS A MEMBER OF THE MEDICAL PROFESSION:

  • I SOLEMNLY PLEDGE to dedicate my life to the service of humanity;

  • THE HEALTH AND WELL-BEING OF MY PATIENT will be my first consideration;

  • I WILL RESPECT the autonomy and dignity of my patient;

  • I WILL MAINTAIN the utmost respect for human life;

  • I WILL NOT PERMIT considerations of age, disease or disability, creed, ethnic origin, gender, nationality, political affiliation, race, sexual orientation, social standing, or any other factor to intervene between my duty and my patient;

  • I WILL RESPECT the secrets that are confided in me, even after the patient has died;

  • I WILL PRACTISE my profession with conscience and dignity and in accordance with good medical practice;

  • I WILL FOSTER the honour and noble traditions of the medical profession;

  • I WILL GIVE to my teachers, colleagues, and students the respect and gratitude that is their due;

  • I WILL SHARE my medical knowledge for the benefit of the patient and the advancement of healthcare;

  • I WILL ATTEND TO my own health, well-being, and abilities in order to provide care of the highest standard;

  • I WILL NOT USE my medical knowledge to violate human rights and civil liberties, even under threat;

  • I MAKE THESE PROMISES solemnly, freely, and upon my honour.