Tag Archives: stroke

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

PURE Study Further Exonerates Dairy Fat: Undeterred, The AHA Persists In Vilifying All Saturated Fat

The skeptical cardiologist had been avoiding reader pleas to comment on a paper recently published in the Lancet from the PURE study which showed that full fat dairy consumption is associated with a lower risk of mortality and cardiovascular disease. It felt like beating a dead horse since  I’ve been writing for the last 5 years that the observational evidence nearly unanimously shows that full fat dairy is associated with less abdominal fat, lower risk of diabetes and lower risk of developing vascular complications such as stroke and heart attack. However, since bad nutritional advice in this area stubbornly persists and the PURE study is so powerful and universally applicable, I felt compelled to post my observations.

What Did the PURE Study Show?

The PURE (Prospective Urban Rural Epidemiology)  study enrolled 136, 00 individuals aged 35–70 years from 21 countries in five continents. Dietary intakes of dairy products ( milk, yoghurt, and cheese) were recorded.. Food intake was stratified  into whole-fat and low-fat dairy. The primary outcome was the composite of mortality or major cardiovascular events.

Consumption of 2 servings of dairy per day versus none was associated with a 16% lower risk of the primary outcome. The high dairy consumers had an overall 17% lower risk of dying. They had a 34% lower risk of stroke.

People whose only dairy consumption consisted of  whole-fat products had a significantly lower risk of the composite primary endpoint (29%).

Here’s how one of the authors of the PURE study summarized his findings (quoted in a good summary at TCTMD)

“We are suggesting that dairy consumption should not be discouraged,” lead investigator Mahshid Dehghan, PhD (McMaster University, Hamilton, Canada), told TCTMD. “In fact, it should be encouraged in low-to-middle income countries, as well as in high-income countries among individuals who do not consume dairy. We have people in North America and Europe who are scared of dairy and we would tell them that three servings per day is OK. You can eat it, and there are beneficial effects. Moderation is the message of our study.”

 

Despite these recent  findings and the total lack of any previous data that indicates substituting low or no fat dairy for full fat dairy is beneficial,  the American Heart Association (AHA)and major nutritional organizations continue to recommend skim or low fat cheese, yogurt and milk over full fat , non-processed  dairy products.

The AHA Continues Its Misguided Vilification Of All Saturated Fat

Medpage today quoted an AHA spokesman as saying in response to the PURE study:

“Currently with the evidence that we have reviewed, we still believe that you should try to limit your saturated fat including fat that this is coming from dairy products,” commented Jo Ann Carson, PhD, of UT Southwestern Medical Center in Dallas and a spokesperson for the American Heart Association.

“It is probably wise and beneficial to be sure you’re including dairy in that overall heart-healthy dietary pattern, but we would continue to recommend that you make lower fat selections in the dairy products,” Carson told MedPage Today regarding the study, with which she was not involved.

 

What is their rationale? A misguided focus on macronutrients. For decades these people have been preaching that saturated fat is bad and unsaturated fat is good. All saturated fat is bad. All unsaturated fat is good.

To deem even one product which contains a significant amount of saturated fat as acceptable would undermine the public’s confidence in the saturated fat dogma.

Bad Nutritional Advice From The AHA Is Not New

Of course, the AHA has been notoriously off base on its nutritional advice for decades. selling its “heart-check” seal of approval to sugar-laden cereals such as Trix, Cocoa Puffs, and Lucky Charms and promoting trans-fat laden margarine. These products could qualify as heart-healthy because they were low in cholesterol and saturated fat.

To this day, the AHA’s heart-check program continues to promote highly processed junk food as heart-healthy while raking in millions of dollars from food manufacturers.

The AHA’s heart-check program is still using low cholesterol as a criteria for heart-healthy food whereas the 2015 Dietary Guidelines concluded that dietary cholesterol intake was no longer of concern.

Why would anyone believe the AHA’s current nutritional advice is credible given the historical inaccuracy of the program?

I’ve noticed that the dairy industry has done nothing to counter the idea that Americans should be consuming skim or low fat dairy product and discussed this with a dairy farmer who only sells full fat products a few years ago.

I posted his comments on this in my blog In April, 2016 and thought I would repost that posting for newer readers below:

 

The Skim Milk Scam:Words of Wisom From a Doctor Dairy Farmer

 

Full fat dairy is associated with less abdominal fat, lower risk of diabetes and lower risk of developing vascular complications such as stroke and heart attack.
quart_whole_milk_yogurt-293x300I’ve been consuming  full fat yogurt and milk  from Trader’s Point Creamery in Zionsville, Indiana almost exclusively since visiting the farm and interviewing its owners a few years ago.

Dr. Peter(Fritz) Kunz, a plastic surgeon, and his wife Jane, began selling milk from their farm after researching methods for rotational grazing , a process which allows  the cows to be self-sustaining: the cows feed themselves by eating the grass and in turn help fertilize the fields,  . After a few years of making sure they had the right grasses and cows, the Kunz’s opened Traders Point Creamery in 2003.

Two more studies (summarized nicely on ConscienHealth, an obesity and health blog)  came out recently solidifying the extensive data supporting the health of dairy fat and challenging the nutritional dogma that all Americans should be consuming low-fat as opposed to full fat dairy.

The Dairy Industry’s Dirty Little Secret

Dr. Kunz opened my eyes to the dirty little secret of the dairy industry when i first talked to him: dairy farmers double their income by allowing milk to be split into its fat and non-fat portions therefore the industry has no motivation to promote full fat dairy over nonfat dairy.

Recently, I  presented him with a few follow-up questions to help me understand why we can’t reverse the bad nutritional advice to consume low-fat dairy.

Skeptical Cardiologist: “When we first spoke and I was beginning my investigation into dairy fat and cardiovascular disease you told me that most dairy producers are fine with the promotion of non fat or low fat dairy products because if consumers are choosing low fat or skim dairy this allows the dairy producer to profit from the skim milk production as well as the dairy fat that is separated and sold for butter, cheese or cream products.”
I  don’t have a clear idea of what the economics of this are. Do you think this, for example, doubles the profitability of a dairy?

Dr. Kunz: “Yes, clearly. Butter, sour cream, and ice cream are highly profitable products… All these processes leave a lot of skim milk to deal with, and the best opportunity to sell skim milk is to diet-conscious and heart-conscious people who believe fat is bad.”

Skeptical Cardiologist:” I’ve been baffled by public health recommendations to consume low fat dairy as the science would suggest the opposite. The only reason I can see that this persists is that the Dairy Industry Lobby , for the reason I pointed out above, actually has a vested interest from a profitability standpoint in lobbying for the low fat dairy consumption.. Do you agree that this is what is going on? ”

 
Dr. Kunz: “Yes, definitely. The obsession with low-fat as it relates to diet and cardiac health has been very cleverly marketed. Fat does NOT make you fat.

Skeptical Cardiologist: “Also, I have had trouble finding out the process of production of skim milk. I’ve come across sites claiming that the process involves injection of various chemical agents but I can’t seem to find a reliable reference source on this. Do you have any information/undestanding of this process and what the down sides might be? I would like to be able to portray skim milk as a “processed food” which, more and more, we seem to be recognizing as bad for us.”

 

Dr. Kunz: “The PMO pasteurized milk ordinance states that when you remove fat you have to replace the fat soluble vitamins A & D. Apparently the Vitamin A & D have to be stabilized with a chemical compound to keep them miscible in basically an aqueous solution. The compound apparently contains MSG!! We were shocked to find this out and it further confirmed that we did not want to do a reduced fat or skim milk product.”

Skeptical Cardiologist: ” Any thoughts on A2? Marion Nestle’, of Food Politics fame, was recently in Australia where there is a company promoting A2 milk as likely to cause GI upset. It has captured a significant share of the Aussie market.”

 

Dr. Kunz: “We have heard of this and have directed our farm to test and replace any A1 heterozygous or homozygous cows.  We believe that very few of our herd would have A1 genetics because of the advantage of using heritage breeds like Brown Swiss and Jersey instead of Holstein.  Because few people are actually tested for lactose intolerance and because of the marketing of A2, it’s imperative not to be left behind in this – whether or not it turns out to be a true and accurate cause of people’s GI upset.

Skeptical Cardiologist:” I like that your milk is nonhomogenized. Seems like the less “processing” the better for food.  I haven’t found any compelling scientific reasons to recommend it to my patients, however. Do  you have any?”

 

Dr. Kunz: The literature is fairly old on this subject, but xanthine oxidase apparently can become encapsulated in the fat globules and it can be absorbed into the vascular tree and cause vascular injury.  I will look for the articles.  Anyway, taking your milk and subjecting it to 3000-5000 psi (homogenization conditions) certainly causes damage to the delicate proteins and even the less delicate fat globules.  Also remember that dietary cholesterol is not bad but oxidized cholesterol is very bad for you. That’s why overcooking egg yolks and high pressure spray drying to make powder products can be very dangerous – like whey protein powders that may contain some fats.

Skeptical Cardiologist: I spend a fair amount of time traveling in Europe and am always amazed that their milk is ultrapasteurized and sits unrefrigerated on the shelves. any thoughts on that process versus regular pasteurization and on pasteurization in general and its effects on nutritional value of dairy.

Dr. Kunz :“Absolutely crazy bad and nutritionally empty.. don’t know why anyone would buy it. The procedure is known as aseptic pasteurization and is how Nestle makes its wonderful Nesquik. If they made a full fat version of an aseptically pasteurized product it may have more oxidized cholesterol and be more harmful than no fat!!”
So there you have it, Straight from the  doctor dairy farmer’s mouth:
Skimming the healthy dairy fat out of  milk is a highly profitable process. Somehow, without a shred of scientific support,  the dairy industry, in cahoots with misguided and close-minded nutritionists, has convinced the populace that this ultra-processed skim milk pumped full of factory-produced synthetic vitamins is healthier than the original product.
Lactosingly Yours
-ACP
The two  recent articles (mentioned in this post) supporting full fat dairy are:

Circulating Biomarkers of Dairy Fat and Risk of Incident Diabetes Mellitus Among US Men and Women in Two Large Prospective Cohorts

which concluded ‘In two prospective cohorts, higher plasma dairy fatty acid concentrations were associated with lower incident diabetes. Results were similar for erythrocyte 17:0. Our findings highlight need to better understand potential health effects of dairy fat; and dietary and metabolic determinants of these fatty acids

and from Brazilian researchers

Total and Full-Fat, but Not Low-Fat, Dairy Product Intakes are Inversely Associated with Metabolic Syndrome in Adults1

Revisiting Who Should Take Aspirin

Four years ago the skeptical cardiologist wrote the (in his extremely humble  and biased opinion) the definitive post on aspirin and cardiovascular disease.  Entitled “Should I take aspirin to prevent stroke or heart attack“,  it pointed out that although Dr. Oz had recently told almost all middle-aged women to take a baby aspirin and fish oil, there was, in fact no evidence to support that practice.

The publication of the ASPREE (Aspirin in Reducing Events in the Elderly) trial results in the latest issue of the New England Journal of Medicine further strengthens the points I made in 2014.

Between 2010 and 2014 the ASPREE investigators enrolled over 19,000 community-dwelling persons in Australia and the United States who were 70 years of age or older (or ≥65 years of age among blacks and Hispanics in the United States) and did not have cardiovascular disease, dementia, or disability.

(It’s important to look closely at the precise inclusion and exclusion criteria in randomized studies  to understand fully the implications of the results (for example, what qualified as cardiovascular disease) and I’ve listed them at the end of this post.)

Study participants were randomly assigned to receive 100 mg of enteric-coated aspirin or placebo. At the end of the study about 2/3 of participants in both groups were still taking their pills.

When I wrote about aspirin in 2014 I focused on cardiovascular disease. At that time, there was some reasonable evidence that aspirin might lower the risk of colorectal cancer. But when we look at outcomes the bottom line is how the drug influences the overall mix of diseases and deaths.

The ASPREE researchers chose disability-free survival, defined as survival free from dementia or persistent physical disability (inability to perform or severe difficulty in performing at least one of the six basic activities of daily living that had persisted for at least 6 monthas their primary end-point which makes a lot of sense-patients don’t want to just live longer, they want to live longer with a good quality of life. If aspirin, to take a totally hypothetical example) is stopping people from dying from heart attacks but making them demented it’s not benefiting them overall.

After 5 years there was no difference in the rate of death, dementia or permanent physical disability between the aspirin group (21.5 events per 1000 person-years) and placebo group (21.2 per 1000).

However those taking aspirin had a significantly higher rate of major bleeding (3.8%) than those taking placebo (2.8%).

The risk of death from any cause was 12.7 events per 1000 person-years in the aspirin group and 11.1 events per 1000 person-years in the placebo group.. Cancer was the major contributor to the higher mortality in the aspirin group, accounting for 1.6 excess deaths per 1000 person-years.

Screen Shot 2018-09-19 at 9.26.41 AM

And, despite prior analyses suggesting aspirin reduces colorectal cancer the opposite was found in this study. Aspirin takers were 1.8 times more likely to die from colorectal cancer and 2.2 times more likely to die from breast cancer.nejmoa1803955_t2

 

Did Aspirin Reduce Cardiovascular Events?

No. It did not.

A separate paper analyzed cardiovascular outcomes

After a median of 4.7 years of follow-up, the rate of cardiovascular disease was 10.7 events per 1000 person-years in the aspirin group and 11.3 events per 1000 person-years in the placebo group (hazard ratio, 0.95; 95% confidence interval [CI], 0.83 to 1.08). The rate of major hemorrhage was 8.6 events per 1000 person-years and 6.2 events per 1000 person-years, respectively (hazard ratio, 1.38; 95% CI, 1.18 to 1.62; P<0.001).

The ASPREE study confirms what I advised in 2014 and hopefully will further reduce the inappropriate consumption of aspirin among low risk individuals.

I’ve taken more patients off aspirin since 2014 than I’ve started on and what I wrote then remains relevant and reflects my current practice. Especially in light of the increase cancer risk noted in ASPREE patients should only take aspirin for good reasons.

Below is my 2014 post entitled “Should I Take Aspirin To Prevent Heart Attack or Stroke.”

Aspirin is a unique drug, the prototypical  two-edged sword of pharmaceuticals. It t has the capability of stopping platelets, the sticky elements in our blood, from forming clots that cause strokes and heart attacks when arterial plaques rupture, but it increases the risk of serious bleeding into the brain or from the GI tract. Despite these powerful properties, aspirin is available over the counter and is very cheap, thus anyone can take it in any dosage they want. 

Who Should Take Aspirin?

For the last five years I’ve been advising my patients who have no evidence of atherosclerotic vascular disease against taking aspirin to prevent heart attack and stroke. Several comprehensive reviews of all the randomized trials of aspirin had concluded by 2011 that

The current totality of evidence provides only modest support for a benefit of aspirin in patients without clinical cardiovascular disease, which is offset by its risk. For every 1,000 subjects treated with aspirin over a 5-year period, aspirin would prevent 2.9 MCE and cause 2.8 major bleeds.

(MCE=major cardiovascular events, e.g. stroke, heart attack, death from cardiovascular disease)

Dr. Oz, on the other hand, came to St. Louis in 2011 to have  lunch with five hundred women and advised them all to take a baby aspirin daily (and fish oil, which is not indicated for primary prevention as I have discussed here). When I saw these women subsequently in my office I had to spend a fair amount of our visit explaining why they didn’t need to take aspirin and fish oil.

After reviewing available data, the FDA this week issued a statementrecommending against aspirin use for the prevention of a first heart attack or stroke in patients with no history of cardiovascular disease (i.e. for primary prevention). The FDA pointed out that aspirin use is associated with “serious risks,” including increased risk of bleeding in the stomach and brain. As for secondary prevention for people with cardiovascular disease or those who have had a previous heart attack or stroke (secondary prevention), the available evidence continues to support aspirin use.

Subclinical Atherosclerosis and Aspirin usage

As I’ve discussed previously, however, many individuals who have not had a stroke or heart attack are walking around with a substantial burden of atherosclerosis in their arteries. Fatty plaques can become quite advanced in the arteries to the brain and heart before they obstruct blood flow and cause symptoms. In such individuals with subclinical atherosclerosis aspirin is going to be much more beneficial.

 

Guided Use of Aspirin

zerilloplaque
Large, complex atherosclerotic plaque in the carotid artery found by vascular screening in an individual with no history of stroke, heart attack, or vascular disease. This patient will definitely benefit from daily aspirin to prevent stroke or heart attack

We have the tools available to look for atherosclerotic plaques before they rupture and cause heart attacks or stroke. Ultrasound screening of the carotid artery, as I discussed here, is one such tool: vascular screening is an accurate, harmless and painless way to assess for subclinical atherosclerosis.

Coronary calcium is another, which I’ve written extensively about.

In my practice, the answer to the question of who should or should not take aspirin is based on whether my patient has or does not have significant atherosclerosis. If they have had a clinical event due to atherosclerotic cardiovascular disease (stroke, heart attack, coronary stent, coronary bypass surgery, documented blocked arteries to the legs) I recommend they take one 81 milligram (baby) uncoated aspirin daily. If they have not had a clinical event but I have documented by either

  • vascular screening (significant carotid plaque)
  • coronary calcium score (high score (cut-off is debatable, more on this in a subsequent post)
  • Incidentally discovered significant plaque in the aorta or peripheral arteries (found by CT or ultrasound done for other reasons)

then I recommend a daily baby aspirin (assuming no high risk of bleeding).

There are no randomized trials testing this approach but in the next few years several large aspirin trials will be completed and hopefully we will get a better understanding of who benefits most from aspirin for primary prevention.

Until then remember that aspirin is a powerful drug with potential for good and bad effects on your body. Only take it if you and your health care provider have decided the benefits outweigh the risks after careful consideration of your particular situation

Acetylsalicylically Yours,

-ACP

 

The inclusion criteria for ASPREE define significant cardiovascular disease as follows

a past history of cardiovascular or cerebrovascular event or established CVD, defined as myocardial infarction (MI), heart failure, angina pectoris, stroke, transient ischemic attack, >50% carotid stenosis or previous carotid endarterectomy or stenting, coronary artery angioplasty or stenting, coronary artery bypass grafting, abdominal aortic aneurysm

What You Should Know About Lipoprotein(a) And Heart Attack Risk

If you have had a heart attack at an early age or one of your parents did but your standard risk factors for coronary heart disease are normal you should consider getting tested for Lipoprotein(a) or Lp(a).

The standard lipid profile that most patients get checks LDL (bad) HDL (good) and total cholesterol along with  triglycerides. While these are useful, I have many patients who have normal standard values but have developed advanced coronary heart disease at an early age despite following a perfect lifestyle (not smoking, regular aerobic exercise, healthy diet.)

The skeptical cardiologist tests such patients for Lp(a) (pronounced LP little a)  and it is quite frequently elevated.

For patients, these are the facts to know about Lp(a)

  1. It is the strongest single inherited (monogenetic) risk factor for the early development of coronary artery disease, heart attacks and strokes.
  2. In addition to increasing risk of atherosclerosis, high Lp(a) is strongly associated with the development of calcific aortic valve disease which can result in narrowing of the aortic valve and aortic stenosis.
  3. Depending on the cut-off used  up to one in five individuals may have elevated Lp(a)
  4. Levels of Lp(a) can be measured with a simple blood test that should cost no more than 50 to 100$. This is not included in standard lipid or cholesterol testing.
  5. Risk for heart attack starts to rise with levels above 30 mg/dl and Canadian guidelines from 2016 (see here)) consider >30 mg/dl to be a risk factor and they recommend measuring Lp(a) in those with a family history of premature CAD or those at intermediate risk.
  6. The European Atherosclerosis Society (EAS, 2010), suggested levels of <50 mg/dl as optimal. The EAS advised measuring Lp(a) once in all patients with premature CVD.
  7. As levels get even higher risk also rises as these graphs show

 

 

 

 

Treatment For High Lp(a)

The lifestyle changes (both exercise and diet) that improve bad and good cholesterol levels have no effect on Lp(a). Our best drugs, the statins, for reducing risk of heart attack and stroke also don’t lower Lp(a) levels.

Only niacin has been shown to reduce Lp(a) across broad populations but there is no evidence that Lp(a) lowering by niacin lowers cardiovascular risk so it cannot be recommended for treatment.(In the AIM-HIGH study niacin did not reduce cardiovascular events in patients with Lp(a) with levels>50 mg/dl, despite achieving a mean Lp(a) reduction of 39%.)

Cholesteryl ester transfer protein inhibitors which raise HDL levels also reduce lipoprotein(a) concentrations, but three such inhibitors have not shown a clinical benefit.

In fact, currently there are no studies showing that lowering Lp(a) with any drug will effectively lower the associated risk of heart attack, stroke and aortic stenosis.

In the not too distant future, effective therapies may emerge. There are promising newer agents (antisense oligonucleotides or ASOs) currently in clinical trials and in limited populations the PCSK9 inhbitors, mipomersen and estrogen have lowered Lp(a) levels.

Why Test For Lp(a)?

If we have no effective therapies that work by lowering Lp(a) why recommend testing for it?

I test Lp(a) for  two reasons.

First, since it is inherited, patients with high levels should consider having first degree relatives tested for Lp(a) to identify those who are going to be at high risk. This provides an early warning of who in the family is most at risk for cardiovascular complications early in life. Such patients should be considered for early screening for subclinical atherosclerosis. In addition, they should be additionally motivated to do everything possible to reduce their elevated risk by lifestyle changes.

Second, I tend to recommend  more aggressive cholesterol lowering in patients who have evidence for early plaque build up for atherosclerotic events early in life than I otherwise would be.     I tend to agree with the approach diagrammed below:

 

With this approach for patients who have had events related to atherosclerosis or advanced CAC for age we work super aggressively on optimizing all risk factors. I try to lower LDL to <70 with statins and with the addition of ezetimibe or PCSK9 inhbitors if needed.

If the patient has more problems with atherosclerotic events despite optimizing risk factors and Lp(a) >60 mg/dl, some experts recommend using apheresis a technique which runs the patient’s blood through a filter which removes LDL and Lp(a). Personally, I have not sent any patients for apheresis and await better studies proving its benefit.

Antiproatherogenically Yours,

-ACP

For those patients seeking more detailed information and references I recommend Dr. Siggurdson’s excellent post on Lp(a)

There is a Lipoprotein(a) Foundation with reasonably informative and accurate website you can peruse here for more information.

Finally, if you want to delve deeply into the data check out this recent JACC review here.

The graphs above and this figure
showing the proposed pro-inflammatory, pro-atherogenic and pro-thrombotic pathways of Lp(a) are from that article.

 

Blood Thinners (Oral Anticoagulants) For Atrial Fibrillation: Who Should Take Them and Which One To Take

The most serious  adverse consequence of having atrial fibrillation is stroke. Since we have safe and effective ways of preventing afib-related stroke with oral anticoagulant drugs (blood thinners), a major decision for the newly diagnosed patient with atrial fibrillation is “should I take a blood thinner?”

To answer this question the afibber should engage in a lengthy discussion with his/her health-care provider which results in a shared and informed  decision. Such discussion must cover your risk of stroke, the benefits of blood thinners in preventing stroke, the bleeding risks of blood thinners and the pros and cons of the five oral anticoagulants available to prevent stroke.

Estimating Your Risk of Stroke With Afib

The best way we have of estimating a patient’s risk of stroke if they have atrial fibrillation (AF) is by the CHA2DS2-VASc scale (which I like to call the Lip scale)

Stroke Risk EstimationThis scale take the factors we know that increase the risk of stroke and assigns 1 or 2 points. The acronym comes from the first letter of the factors that are known to increase risk as listed to the left.

Most of the factors get 1 point, but prior stroke (S) and age>75 (A) get 2 points.

We then add up your points and use another chart (or app) to calculate the risk of stroke per year.

CHA2 stroke riskYour risk of stroke is very low if you have zero risk factors; it gets progressively higher as you reach the maximum number of 9.

Treatment with an oral anticoagulant (OAC),  either warfarin, or one of the four novel anticoagulant agents (NOACS), is recommended when score is >/=2 corresponding to a  risk of stroke  above 1-2% per year.

These blood thinners have consistently been shown to lower your risk of stroke or systemic embolization (when a clot from the heart goes somewhere other than the brain) by almost 70%.

The higher the risk, the more the benefit of these blood thinners in preventing stroke.

Both European and American guidelines recommend using the CHA2DS2-VASc score for initial risk stratification. The European  guideline recommends OAC therapy for males with a CHA2DS2-VASc score ≥1 and for female patients with a score ≥2., whereas the American guideline recommends use of OAC if the CHA2DS2-VASc  score is ≥2 for men and women.

I’ve been using the CHA2DS2-VASc scale for several years in my afib patients. I try to review the patient’s risk of stroke and their risk of bleeding during every office visit, and decide whether they should be on or off an OAC.

Bleeding From Blood Thinners

All OACs cause increase bleeding. They don’t discriminate between bad clots that cause strokes and good clots that stop you from bleeding.

If you’re taking one you are more likely to have nose bleeds, bleeding into the intesitnal tract or urine and you will bleed longer when cut and more profusely if in an accident. In lower stroke risk patients, the bleeding risk of OAC of 1% per year may outweigh the benefits conferred by stroke reduction.

I wrote a post entitled “Why Does The TV Tell me Xarelto Is a Bad Drug” which points out that law suits against the makers of the newer OACs are frivolous and that these NOACs are likely more safe and effective than warfarin.

In recent years, four new drugs for reducing strokes in patients with atrial fibrillation which are much less influenced by diet and medications have gained approval from the FDA. These are generally referred to as “novel anticoagulants” reflecting their newness, different effects from warfarin or aspirin, and their blood thinning properties.  The first  (brand name Pradaxa) was released to much excitement and fanfare in October, 2010.  The press release for this approval read as follows:

PRADAXA, an oral direct thrombin inhibitor2 that was discovered and developed by Boehringer Ingelheim, is the first new oral anticoagulant approved in the U.S. in more than 50 years. As demonstrated in the RE-LY® trial, PRADAXA 150mg taken twice daily has been shown to significantly reduce stroke and systemic embolism by 35 percent beyond the reduction achieved with warfarin, the current standard of care for patients with non-valvular atrial fibrillation. PRADAXA 150mg taken twice daily significantly reduced both ischemic and hemorrhagic strokes compared to warfarin

What was very clear from the study with Pradaxa  and stated very clearly in all publications and patient and doctor  information sources was that just like warfarin, patients could have severe bleeding complications, sometimes fatal. Overall serious bleeding complications were about the same (the rate of major bleeding in patients Pradaxa  in the RE-LY trial was 3.1% versus 3.4% in the warfarin group) but Pradaxa had about 50% more bleeding from the gastrointestinal tract and warfarin about 50% more bleeding into the brain.

Another big difference between the novel anticoagulants and warfarin is that we have antidotes (Vitamin K, fresh frozen plasma) that can reverse the anticoagulation state rapidly for warfarin but until recently none for the newer drugs. (There is now available an antidote for Pradaxa).  This information also was made very clear to all doctors prescribing the medications in the package insert and educational talks. Despite this, in the major trials comparing these newer agents to warfarin, the newer agents were as safe or safer than warfarin.

The most feared bleeding complication on all OACs is bleeding into the head (intracranial hemorrhage). The risk of ICH is between 0.2 to 0.4 percent per year on warfarin. Studies show with the NOACs the risk is about half of the risk on warfarin.

Should You Take a NOAC or Warfarin?

Once the decision has been made to start a blood thinner, the next question is whether to take warfarin or a NOAC. Warfarin (brand name Coumadin) has been utilized since the 1950s  and prior to 2010 was  the only drug available for doctors to reduce clot formation in the heart and susbsequent strokes.. Warfarin is only effective and safe within a narrow window and its effects are strongly influenced by Vitamin K in the diet and most medications. Thus, frequent blood testing and adjustment in dosage is needed, and close monitoring of diet and changes in medications. Even with this close monitoring, serious and sometimes fatal bleeding occurs frequently with warfarin.

Here is a patient information sheet on warfarin which gives you an idea of issues you will need to be aware of when taking the drug. (WArfar patient handout)

If you do a Google search on warfarin you will quickly discover that it is used as a rat poison. Scientists isolate the chemical from  sweet clover that was causing cows to bleed and then developed a more potent form that they named warfarin in the 1940s. After developing blood tests that allowed the drug to be used safely  to dissolve clots it was approved for human use in the 1950s.

Warfarin or more potent variations on its chemical structure have been utilized as rat poison since the 1940s.

The rats are consuming much larger quantities of the blood thinner and are clearly not being monitored for blood thinness.

Some despicable sites peddling alternative or natural products such as this “Healthy Habits” site engage in fear-mongering over the warfarin/rat poison connection in order to promote totally unproven products. Healthy Habits indirectly suggests  that Nattokinase : is a safer, more effective natural alternative to warfarin” This remarkable enzyme has the ability to dissolve blood harmful clots involved in heart disease and strokes without upsetting normal healthy clotting.”

Such misinformation is dangerous and could lead to patients stopping a life-saving medication and suffering a stroke.

By the way, in this Xarelto (another NOAC competitor) ad, Screen Shot 2016-06-29 at 2.21.20 PMKevin Nealon says he chose Xarelto over warfarin because he wanted to eat salads. This is a common misconception and the makers of Xarelto should be ashamed for promulgating it.

I tell my patients it is fine to eat green, leafy vegetables while taking warfarin. The Vitamin K in the vegetables does influence the effectiveness of warfarin thinning blood but this is why we check the blood test to determine the appropriate dosage of warfarin for you and your personal dietary Vitamin K consumption , be it high or low.

Novel Oral Anticoagulant Drugs

The newer OACs, in contrast to warfarin do not require blood tests for monitoring of their efficacy because their levels are not significantly influenced by changes in diet or most medications.

In head to head studies versus warfarin four of these NOACs have demonstrated at least similar efficacy in preventing stroke and at most similar bleeding risk.

Due to their perceived advantages most new prescriptions for OACs are for NOACs. In contrast to 2014 American afib guidelines which don’t state a preference, the most recent European afib guidelines recommend choosing a NOAC over warfarin when initiating anticoagulant therapy in patients who are eligible for NOACs. (Ineligible patients include those with mitral stenosis, mechanical heart valves and end-stage renal disease.)

The ESC guidelines published in 2016, , make choosing a NOAC over warfarin a IA recommendation. This means there is a consensus that the treatment should be recommended (Class I recommendation) and that there is strong evidence from randomized controlled trials to support it (Level A.)

I have decided to primarily use Eliquis (apixaban) as my NOAC of choice based on my comparison of the different NOAC studies. If a patient’s insurance covers another NOAC better , making it cheaper then  I am happy to switch.

Because these four NOACs are new and brand name they are significantly more expensive than warfarin. Cost varies substantially based on type of insurance coverage and we can only determine how much a patient will pay for any given NOAC based on writing a prescription and having a pharmacy check out the cost.

I have found some patients paying nothing for their NOAC whereas some are paying several hundred dollars monthly. The more NOACs cost, the more likely the patient and I are to choose warfarin.

While waiting to determine if cost is going to be prohibitive I will typically provide the patient with samples of the NOAC chosen. The pharmaceutical companies making these NOACs are clearly making substantial profits off them and they are happy to provide lots of samples to doctors to influence the doctors to utilize their product.

NOACs are being extensively promoted both to physicians and directly to patients. Physicians have to be especially careful to make sure they are presenting a true summary of the relative risks and benefits of warfarin versus NOACs in light of these constant attempts to influence them.

Despite now having four NOACs with similar benefits and ease of use compared to warfarin, the cost of these agents doesn’t seem to have declined significantly from when the first NOAC came on the market. Personally, I would love to see Medicare step in and negotiate significantly lower costs for American senior citizens.

An abstract at the ACC meeting in March of 2017 suggested  a reduction in medical costs with NOACs despite their high costs. This was related to a lower rate of major bleeding complications: Xarelto cost $542 per patient compared with warfarin’s $500, or $42 more. Pradaxa, cost $367 to warfarin’s $452, saving $85.  Eliquis cost  $286 charge against warfarin’s $537 resulting in $251 in savings. Data were from from a study of U.S. Medicare patient records.

Aspirin May Not  Prevent Stroke In Afib

Many patients consider aspirin to be  a “blood thinner” that has some benefit in preventing clots and strokes in patients with afib. However,  aspirin is not considered a blood thinner or anticoagulant and is more properly  termed an anti-platelet agent.

I used to consider aspirin at doses of 120 to 200 mg daily provided some protection against stroke in afib and put afib patients on aspirin who were low risk for stroke or would not or could not take OACs.

More and more, however, experts are reaching the conclusion that the substantial bleeding complications from aspirin usage outweigh its very slight benefit in stroke prevention.

The most recent ESC guidelines, in fact, list aspirin therapy for stroke prevention in atrial fibrillation as IIIA. That means that overall it is felt to be harmful (III) with a high level of evidence (A.)

Bleeding risks for aspirin are similar to warfarin and Eliquis. Thus, patients should not consider aspirin as a safer alternative to prevent stroke in afib.

Finally, do not take any “natural” supplement that has been promoted as a blood thinner. These are neither safe nor effective. Remember that it took years of scientific investigation and careful testing in animals then humans before warfarin (the agent in sweet clover that caused cows to bleed ) was transformed into a safe and effective anticoagulant.

Antiemboligenically yours

-ACP

Is September Really National Atrial Fibrillation Awareness Month (And Why Does It Matter?)

The skeptical cardiologist received an email from a woman telling him that September is atrial fibrillation awareness month and offering me the free use of an infographic given that I

“care deeply about helping people living with AF.”

Well, I do care about deeply about people living with atrial fibrillation and pretty much all cardiac diseases  (except perhaps Schuckenbuss syndrome.)

That’s the major reason I write this blog. I’ve written a lot about Afib and have a lot more i want to write (I really want to write about antiarrhythmic drugs, i.e. drugs that maintain you in normal sinus rhythm.)

But I don’t find it particularly helpful to assign a disease to a month or a day so my posts on atrial fibrillation come out randomly dependent on the mysterious machinations of my messy mind.

It turns out that September, 2009 was declared National Atrial Fibrillation Awareness Month (NAFAM) by Senate Resolution 262 although Stop Afib.org wants us to believe September is eternally NAFAM.

However, the email prompted me to better organize my atrial fibrillation and stroke page (now containing all that I have written on the subjects) which I have copied below.

Posts on Diagnosing Atrial fibrillation

Take your pulse and prevent a stroke

TIAs and silent atrial fibrillation. Sometimes strokes present in unusual ways, like the inability to differentiated a spade from a diamond when playing bridge and afib is often the cause.

Estimating Stroke Risk in Patients With Atrial Fibrillation You can estimate your stroke risk using an app that utilizes the CHAD2DS2-VASc score. I prefer to call the Lip score.

Posts About Using Personal Devices To Diagnose Atrial Fibrillation

Two That Work Reasonably Well

AliveCor

Using a Smart Phone Device and App To Monitor Your Pulse for Atrial Fibrillation (AliveCor)

AliveCor Is Now Kardia and It Works Well At Identifying Atrial Fibrillation At Home And In Office

AliveCor Successes and Failures.

Sustained Atrial Fibrillation or Not: The Vagaries and Inaccuracies of AliveCor/Kardia and Computer Interpretation of ECG Rhythm

AfibAlert

How Well Does The AfibAlert Remote Hand-Held Automatic ECG Device Work For Detection of Atrial Fibrillation?

AfibAlert Versus AliveCor/Kardia: Which Mobile ECG Device Is Best At Accurately Identifying Atrial Fibrillation?

And One of Several Devices To Avoid: AF Detect

Do NOT Rely on AF Detect Smartphone App To Diagnose Atrial fibrillation

Posts About Treatment Of Atrial Fibrillation

        Lifestyle Changes

How Obesity Causes Atrial Fibrillation in FatSheep and How Losing Weight helps prevent afib from coming back.

Drug Therapy: Rate Control and Anticoagulation

Foxglove Equipoise. When William Withering began treating patients suffering from dropsy in 1775 with various preparations of the foxglove plant he wasn’t sure if he would help or hurt them. After 240 years of treatment, we are still unsure if the drug obtained from foxglove is useful.

Should Digoxin Still Be Used in Atrial Fibrillation? Recent studies suggest that we should not.

Why Does the TV Tell Me Xarelto Is A BAD Drug? Anticoagulant drugs that prevent the bad clots that cause stroke also increase bleeding risk. A bleeding complication is not a valid reason to sue the manufacturer.  The lawsuit are strictly a money-making tactic for sleazy lawyers.

Cardioversion and Ablation

Cardioversion: How Many Times Can You Shock The Heart?

Ablation: Cautionary Words From Dr. John Mandrola and The Wisdom of a Team Approach

Miscellaneous Topics

What Happens If You Go Into Atrial Fibrillation On A Cruise?

Infographics

Are infographics really helpful? Someone should do a study on that. Perhaps we could use the money we spend on infographics in atrial fibrillation to research whether the left atrial appendage should be excised at the drop of a hat.

Here’s the infographic (because everyone loves an infographic!)

The first part lays out the problem of AF with patriotic bunting.

The second part uses the annoying numerical infographic approach.

 

 

 

 

 

 

 

The third part explains why I got the email. A product is being promoted. The woman who sent me the email works for MyTherapyApp.

 

 

 

Eagerly Awaiting Schuckenbuss Syndrome Day,

-ACP

 

 

 

What Pain Medications Are Safe For My Heart?

The skeptical cardiologist is frequently asked by patients if it is OK to take certain pain medications.

Yesterday, I got a variation on this  when a patient called and indicated that he had been prescribed meloxicam and tramadol by his orthopedic surgeon for arthritic leg joint pain. The orthopedic surgeon said to check with me to see if it was OK to take either of these medications. (Patients, if you want to skip to my answer skip down to the last two sections of the post and avoid the background information.)

What Is The Risk Of Pain Medications?

Cardiologists have been concerned about the increased risk of heart attack and heart failure with non steroidal anti-inflammatory drugs (NSAIDs) since Vioxx was withdrawn from the market in 2004.

NSAIDS have long been known to increase risk of gastrointestinal (GI) bleeding  by up to 4-5 fold, Scientists developed Vioxx, a COX-2 inhibitor, hoping to reduce that risk but Vioxx  turned out to  increase the risk of heart attack.

Since this revelation it has become clear that NSAIDS in general increase the risk of heart problems as well as GI problems

This includes the two over the counter (OTC) NSAIDS:

-ibuprofen (in the US marked most commonly as Motrin or Advil, internationally known as Nurofen). For extensive list of brand names see here.

-naproxen (most commonly sold as Aleve. Per wikipedia “marketed under various brand names, including: Aleve, Accord, Anaprox, Antalgin, Apranax, Feminax Ultra, Flanax, Inza, Maxidol, Midol Extended Relief, Nalgesin, Naposin, Naprelan, Naprogesic, Naprosyn, Narocin, Pronaxen, Proxen, Soproxen, Synflex, MotriMax, and Xenobid. It is also available bundled with esomeprazole magnesium in delayed release tablets under the brand name Vimovo.)

In 2015  the FDA mandated  warning labels on all prescription NSAIDs including

1) a “black box” warning highlighting the potential for increased risk for cardiovascular  (CV) events and serious life-threatening gastrointestinal  bleeding, ulceration, and perforation;

(2) statements indicating patients with, or at risk for, CV disease and the elderly may be at greater risk, and that these reactions may increase with duration of use;

(3) a contraindication for use after coronary artery bypass graft surgery on the basis of reports with valdecoxib/parecoxib;

(4) language that the lowest dose should be used for the shortest duration possible

5) wording in the warning section that there is no evidence that the concomitant use of aspirin with NSAIDs mitigates the CV risk, but that it does increase the GI risk

Since then, hardly a day goes by without me having a discussion with a patient about what drugs they can safely take for their arthritis.

A reasonable approach to using NSAIDS, balancing GI and CV risks, that I have used in the past comes from a 2014 review
This table and many authorities recommend naproxen as the NSAID of choice for patients with high CV risk.

Indeed prior to the publication of the PRECISION study in 2016 I believed that naproxen was the safest NSAID for my cardiac patients. I told them it was OK to use from a CV standpoint but to use the least amount possible for the shortest time in order to minimize side effects.

The PRECISION study compared a COX-2 NSAID (celecoxicib or Celebrex) to ibuprofen and naproxen in patients who required NSAIDS for relief of their joint pain.

The findings:

cardiovascular death (including hemorrhagic death), nonfatal MI, or nonfatal stroke, occurred in 2.3% of celecoxib-treated patients, 2.5% of the naproxen-treated patients, and 2.7% of the ibuprofen group.

There was no placebo in this trial so we can only look at relative CV risk  of the three NSAIDS and it did not significantly differ.

GI bleeding was less with celecoxib than the other two NSAIDS.

Although this study has flaws it throws into question the greater CV safety of naproxen and suggests that all NSAIDS raise CV risk.

My Current Patient Advice on Cardiac Safety of Pain Meds

Here is an infographic I came across from the Arthritis Foundation (complete PDF….here)

It’s a reasonable approach for these OTC drugs and I will start handing this out to my patients.

We should consider that all NSAIDS have the potential for increasing the risk of heart attack and heart failure, raising blood pressure, worsening renal function and causing GI bleeding.

Therefore, if at all possible avoid NSAIDS.

Acetaminophen (Tylenol) is totally safe from a heart standpoint and overall if you don’t have liver disease it is your safest drug for arthritis. However, it provides no anti-inflammatory effects and often is inadequate at pain relief.

Treating The Whole Patient

Meloxicam is an NSAID so my patient should , if at all possible, avoid it.

The other drug he was prescribed, tramadol, is an opiod. Opiods have their own set of problems including, most importantly,  addiction and abuse.

A recent review concluded

 reliable conclusions about the effectiveness of long-term opioid therapy for chronic pain are not possible due to the paucity of research to date. Accumulating evidence supports the increased risk for serious harms associated with long-term opioid therapy, including overdose, opioid abuse, fractures, myocardial infarction, and markers of sexual dysfunction; for some harms, the risk seems to be dose-dependent.

As his cardiologist I am concerned about his heart, of course, but a good cardiologist doesn’t just focus on one organ, he looks at what his recommendations are doing to the whole person.

I certainly don’t want to have him become addicted to narcotics in order to avoid a slightly increased risk of a heart attack. On the other hand, the risks of the NSAIDS involve multiple organs, most of which don’t fall in the domain of the cardiologist.

My patient’s risk of taking either the meloxicam or the tramadol is best assessed by his primary care physician, who has the best understanding of his overall medical condition and the overall risk of dangerous side effects from these drugs.

Ultimately, I think the decision of which pain pill to take for chronic arthritis has to be made by an informed patient in discussion with his  informed (and informative) primary care physician. Only the patient can decide how much pain he is having and how much risk he/she wants to assume in relieving that pain.

Analgesically Yours,

-ACP

Death Knell For Niacin For Lipids Sounded by FDA?

The skeptical cardiologist stopped writing new prescriptions for niacin extended release tablets in 2011. For any patient who was taking niacin, I recommended stopping it.

Because niacin had favorable effects on the cholesterol profile, physicians had been utilizing it for many years in high risk patients on statins who had low HDL  (good cholesterol) and/or high triglycerides.

The rationale was that, since high HDL was associated with lower risk of heart attacks, raising the HDL would lower that risk. Similarly, lowering the triglycerides would improve cardiovascular risks.

While niacin certainly improved the cholesterol profile, there was no good evidence that starting it in a patient already on statin would improve cardiovascular outcomes. The cholesterol profile is a surrogate endpoint: the actual treatment goal is reducing cardiovascular disease.

In 2011, the AIM-HIGH study proved there was no benefit to adding niacin to good statin therapy despite increasing HDL from 35 to 42 mg/dl, lowering triglycerides and lowering LDL. This and other studies showing no benefit of niacin therapy (and worrisome adverse effects) should have resulted in the total cessation of niacin prescriptions, especially  in patients on statins.

Unfortunately, old habits die hard amongst physicians, and the allure of raising HDL and lowering triglycerides with niacin persisted despite a lack of evidence of any benefit in lowering cardiovacular risk.

Yesterday, the FDA announced it was removing from the market two  drugs made by Abbvie, Advicor and Simcor, which are combinations of extended release niacin plus lovastatin or simvastatin, and removed its approved indication for niacin ER plus statin for lowering CHD risk stating:

“Based on the collective evidence from several large cardiovascular outcome trials (Refs. 1-3), the Agency has concluded that the totality of the scientific evidence no longer supports the conclusion that a drug-induced reduction in triglyceride levels and/or increase in HDL-cholesterol levels in statin-treated patients results in a reduction in the risk of cardiovascular events. Consistent with this conclusion, FDA has determined that the benefits of niacin ER tablets and fenofibric acid DR capsules for coadministration with statins no longer outweigh the risks, and the approvals for this indication should be withdrawn.”

This is good news for patients whose physicians were keeping them on the unproven brand name combination drugs, Advicor and Simcor.

There are still legitimate uses of niacin to prevent vitamin deficiencies but If you are still taking some form of niacin ER for the purpose of preventing heart disease with or without a statin I recommend presenting your doctor with the link to the FDA pronouncement above and having a good discussion with him about the rationale for staying on it.

The other drug mentioned in the announcement, fenofibric acid,  is far less often prescribed and is not available as a combination. It is the most effective drug we have for extremely high triglyceride levels over 500 mg/dl which can cause pancreatitis. I have a few patients on the generic fenofibric acid strictly for the purpose of lowering their dangerously high triglycerides but not for the indication of lowering their cardiovascular risk.

Nonsurrogateingly Yours

-ACP

 

Atrial Fibrillation: How Many Times Can You Shock The Heart?

The most effective method for getting a heart that is in atrial fibrillation back to normal rhythm is a called an electrical cardioversion.

I’ve tried to come up with a good alternative or descriptive term for this procedure for my patients, such as “resetting” or “rebooting” the heart, but the term that seems to best resonate with patients is “shocking” the heart.

How Does Electrical  Cardioversion Work?

Typically, we all can connect (excuse the pun) to the feeling of a low current electrical shock which occurs when touching an ungrounded electrical source.

Unless the current reaches a certain level, it only results in transient burns and discomfort.

However, at current levels greater than 50 mA, an AC electrical shock traveling through the chest can, if timed properly, cause the heart to go out of normal rhythm into ventricular fibrillation.

We use a “synchronized” electrical cardioversion (termed direct current or DC cardioversion (DCC)) to convert a fibrillating or fluttering atrium back to the normal rhythm by timing the electrical shock so that it doesn’t cause ventricular fibrillation but resets both ventricles and atria safely back to normal.

cardioversionAF
Recording from a recent cardioversion I performed on a patient with recurrent atrial flutter/fibrillation associated with heart failure. On the left is the heart rhythm before the shock, and on the right we can see resumption of normal sinus rhythm. The little squiggles labeled p waves represent the electrical activity of the sinus node preceding the big vertical deflections, which represent the electrical activity of the ventricles (QRS). The circled little arrow shows the timing of the shock concurrent with the QRS complexes. If the timing is not correct, the shock can cause ventricular fibrillation.

This may seem like a barbaric and unnecessarily crude and dramatic way to restore normal rhythm, but if patients are properly prepared for this procedure, it is very safe and very effective, resulting in resumption of the normal rhythm 99% of the time.

There are some medications that we can utilize to convert atrial fibrillation (afib) back to normal (antiarrhythmic drugs), but they are far less effective than the electrical cardioversion, and often can bring out more dangerous heart rhythms.

Typically, I do my cardioversions in conjunction with an anesthesiologist, who administers IV propofol (yes, this was Michael Jackson’s sleep aid, his “milk”) to obtain “deep  sedation.” At this level of anesthesia, the patient is breathing on his own but will only respond to painful stimulation. The propofol is short-acting and prevents the patient from feeling the intense pain of the cardioversion (often described as like a mule kicking one in the chest), and from recalling any of the events.

Electrical cadioversion
The skeptical cardiologist calmly prepares to push the “shock” button that will trigger the Zoll device to deliver 150 Joules of biphasic direct current to the electrodes attached to his patient’s chest thereby “ZAPPING” her back to NSR. Should the patient’s heart rhythm be too slow, the Zoll device also can serve as an external pacemaker, triggering cardiac contractions via lower level electrical currents delivered through the chest electrodes.

The electrical shock is administered through electrodes, consisting of large sticky pads with electrical conducting gel attached to the right anterior chest and the left posterior back (see this brief information from Zoll about optimal placement).
Since I began using “biphasic” energy, the initial cardioversion is successful >95% of the time in my experience, but the heart may revert back to atrial fibrillation anywhere from a few minutes to a few years after the shock. We can reduce the chances of reverting back by the use of anti-arrhythmic drugs.

Multiple Shocks: What Is The Limit?

The DCC may need to be repeated, and we may repeat it after starting one of those anti-arrhythmic drugs I mentioned, in order to increase the time that the heart stays in the normal rhythm.

A common question when I recommend a repeat cardioversion is:

“Doc, how many times can you have your heart shocked?”

One might think it is one and done with the shock but it is not a cure; it is merely a resetting of the chaotic, confused and futile activity of the atria, so that the synchronized and regular electrical pacing provided by the sinus node in the upper right atrium can again resume its rightful role as conductor of the cardiac electrical orchestra that creates the wondrous symphony of normal cardiac contraction.

The factors that brought on the afib in the first place likely are still present: if we don’t address correctable factors we are less likely to maintain the normal sinus rhythm (NSR). Correctable factors include:

  • abnormal thyroid function
  • abnormal potassium or magnesium
  • inflammation of adjacent lung or pericardium
  • severe infection
  • obesity (see my post on fat sheep and afib)
  • certain cardiac valve problems

There is no evidence that the cardioversion per se damages the heart in any way. The major risks of the procedure (again, assuming proper preparation, see below) are related to the anesthesia.

I am more inclined to recommend a repeat cardioversion if there is clear-cut evidence that the patient does poorly when the heart is in afib.

Why Shock The Heart?

In medicine, there are two reasons for giving medications and doing surgery/procedures: to make the patient feel better or to reduce the chances of dying/having a major complication.

The major complication of afib is stroke.  Proper anticoagulation is required to prevent this in patients with afib whether or not they are in normal rhythm.  Clots can form in the left atrial appendage within hours of the development of afib, and the electrical cardioversion can increase the chance of stroke as any clot present is more likely to be expelled when the quivering, ineffective atrium converts back to a normally pumping, vigorous  atrium.

Primarily, then, we utilize cardioversion for the purpose of making patients feel better.

Some patients feel terrible the moment they go into afib: symptoms of palpitations, chest pain, or shortness of breath predominate and are especially prominent if the heart rate is high. Controlling the high heart rate with beta-blockers or diltiazem will reduce many of these symptoms, but I have a large number of patients who still feel terrible when they are “out of rhythm,” even if the heart rate is normal. Such patients who persist in afib are good candidates for one or multiple cardioversions, with or without the addition of anti-arrhythmic drugs.

A second group of patients, I think, benefits the most from maintaining sinus rhythm (rhythm control strategy): patients who develop heart failure when they go into AF.

These patients may not even know they are in AF because they don’t feel the typical symptoms initially.  After a few days or weeks or months of being in afib silently, however, they develop shortness of breath, weakness and leg  swelling – classic signs of heart failure.

When we look at the heart of such a patient by echocardiography, we often find one of two things causing the heart failure: a weakening of the heart muscle (cardiomyopathy) or significant leakage/backflow from the mitral valve (mitral regurgitation). Following cardioversion and maintenance of SR for weeks to months, the heart muscle strengthens back to normal and/or the mitral regurgitation improves dramatically and the heart failure resolves.

Multiple Shocks: Rationale

Yesterday I did an electrical cardioversion on an elderly patient of mine  for atrial fibrillation/flutter; this was her fifth DCC in the last year.

She falls into the second category of afib patients; she had developed severe heart failure due to mitral regurgitation after silently going into afib a year earlier. After long-term loading on the anti-arrhythmic drug amiodarone, followed by her fourth cardioversion, she had stayed in NSR for 10 months, her MR resolved, and she felt great. In patients like her, I think it is particularly important to maintain NSR and thus, multiple shocks are definitely warranted.

On the other hand, if you feel fine in afib without any evidence that it is effecting your heart muscle or valves, then it is hard to justify multiple attempts to shock the heart.

Any patient that has recurrent symptomatic afib or afib associated with heart failure, should be considered a candidate for an atrial fibrillation ablation.  The risks and benefits of afib ablation are worthy of another blog post, but the patient-centered afib website stopafib.org has a reasonable discussion here. Suffice it to say, it is a much more complicated and risky procedure than a cardioversion, but it attempts to address the underlying cause(s) of afib, and in some cases creates what could be considered a “cure.”

Cardiovertly Yours,

-ACP

For additional reading:

Here’s a good article from the European Society of Cardiology on cardioversion (https://www.escardio.org/Guidelines-&-Education/Journals-and-publications/ESC-journals-family/E-journal-of-Cardiology-Practice/Volume-11/Cardioversion-in-Atrial-Fibrillation-Described)

and check out what Dr. John Mandrola, an electrophyiologist (cardiologist who specializes in electrical problems of the heart) has to say about afib ablations at Drjohnm.org (http://www.drjohnm.org/2015/09/a-cautionary-note-on-af-ablation-in-2015/)

Credits-Life Coach of the Skeptical Cardiologist (LCOSC) for review of electrical engineering stuff.