Increasingly, the skeptical cardiologist has been recommending to patients that they take BP meds at bedtime as evidence has mounted that this does a better job of normalizing asleep blood pressure and minimizing daytime side effects.
Now a study published in European Heart Journal in October has demonstrated that routine ingestion of BP meds at bedtime as opposed to waking results in improved 24 hour BP control with enhanced decrease in asleep BP and increased sleep-time relative BP decline (known as BP dipping.)
More importantly, bedtime BP med ingestion in this randomized trial of over 19 thousand hypertensive Spaniards resulted in highly significant reductions in cardiovascular events including death, heart attack, heart failure and stroke over a 6 year median follow-up
The so-called Hygia Chronotherapy Trial was extremely well done and the results are powerful and should modify clinical practice immediately.
This figure demonstrates the dramatic and highly significant 45% reduction in all types of cardiovascular events measured. Note that stroke rate was halved!
Here are the Kaplan-Meier curves showing early and progressive separation of the treatment curves.
There was no difference side effects or compliance between the two groups.
The remarkable aspect of this intervention is that it costs nothing, introduces no new medications and has no increased side effects.
This study is practice-changing for me. We will be advising all hypertensive patients to take their once daily BP meds at bedtime.
h/t Reader Lee Sacry for bringing this study to my attention
Old habits die hard in medicine. For decades the skeptical cardiologist and his cardiology brethren and sistren have prescribed aspirin to prevent stroke in patients with atrial fibrillation.
For those patients with atrial fibrillation (AF) who were considered low risk it was felt that aspirin provided some benefit in preventing the clots that fly out of the heart (and land in arteries elsewhere in the body) at an acceptably low risk of bleeding. For higher risk patients more powerful and effective agents (oral anticoagulants) are usually recommended.
The American guidelines on AF (2014) gave a IIB recommendation to aspirin. IIB is not a ringing endorsement having been described as “this is our suggestion, but you may want to think about it.”
For patients with nonvalvular AF and a CHA2DS2-VASc score of 1, no antithrombotic therapy or treatment with an oral anticoagulant (OAC) or aspirin may be considered. (Level of Evidence: C)*
Thus, in the 2016 European guidelines on the management of AF the authors state that “the evidence supporting antiplatelet mono therapy (e.g. aspirin or clopidogrel) for stroke prevention in AF is very limited” and the bleeding rate” is similar to OAC”:
Aspirin and other antiplatelets have no role in stroke prevention (III A). The combination of anticoagulation with antiplatelets increases bleeding risk and is only justified in selected patients for a short period of time; for example, in patients with an acute coronary syndrome or stent, balancing the risk of bleeding, stroke and myocardial ischaemia (IIa B/C).
Stroke risk evaluation is based on the CHADS-VASc score. With a score ≥2 in male and ≥3 in female patients, anticoagulation for stroke prevention is clearly recommended, while in a score of 1 in males and 2 in females, anticoagulation should be considered. No antithrombotic therapy of any kind should be prescribed in patients with a CHADS-VASc score of 0 (males) or 1 (females).
Antiplatelet therapy increases bleeding risk, especially dual antiplatelet therapy (2.0% vs. 1.3% with antiplatelet monotherapy; P < 0.001), with bleeding rates that are similar to those on OAC. Thus, antiplatelet therapy cannot be recommended for stroke prevention in AF patients.
“The European guidelines have done away with aspirin for stroke prevention in atrial fibrillation. It barely made it into our current US guidelines. I don’t think aspirin should be in there and I don’t think it will be there in the next guidelines. The role of aspirin will fall away,” said Bernard J. Gersh, MB, ChB, DPhil, Professor of Medicine at the Mayo Clinic in Rochester, Minnesota. “It’s not that aspirin is less effective than the oral anticoagulants, it’s that there’s no role for it. There are no good data to support aspirin in the prevention of stroke in atrial fibrillation.”
“The use of aspirin has probably been misguided, based upon a single trial which showed a profound effect and was probably just an anomaly,” said N.A. Mark Estes III, MD, Professor of Medicine and Director of the New England Cardiac Arrhythmia Center at Tufts University in Boston, and a past president of the Heart Rhythm Society
I would just take it off of your clinical armamentarium because the best available data indicate that it doesn’t prevent strokes. I’m certainly not using it in my patients. Increasingly in my patients with a CHA2DS2-VASc of 1, I’m discussing the risks and benefits of a novel oral anticoagulant,” said Dr. Estes.
Those are amazingly definitive statements. But, as I’ve learned we can’t just except what the “experts” and the guidelines tell us we have to look at the original studies informing these decisions.
It compared warfarin (measured by PT ratio) to placebo and aspirin 325 mg to placebo in preventing stroke in AF patients. Warfarin reduced stroke by 67% and aspirin by 42%. The risk of significant bleeding was similar at around 1.5% per year for all three arms.
Based on this and other AF trials (AFASAK, CAFA, SPINAF, EAFT, et al. ) when I gave talks or taught cardiology fellows in the 1990s my message (similar to this presentation) emphasized the superior benefits of warfarin compared to aspirin (especially when monitored by INR in a 2.0 to 3.0 range) in higher risk AF patients. Overall it was felt that aspirin (dosing varying from 100 to 325 mg) reduced stroke/embolism by 20-30% compared to placebo and would offer benefit to those patients at low risk or who could not tolerate warfarin.
Based on the 2014 American guidelines (and a focused update in 2019 which did not address this issue) I had not been actively taking my low risk patients off baby aspirin.
I was prompted to re-research this question and write this post because a 58 year old woman with paroxysmal AF and hypertension called the office today asking if I wanted her to take a baby aspirin daily. She has a CHADS2VASC score of 2 (woman and hypertension) and falls into the category where we should have an in depth conversation about the risks and benefits of anticoagulant therapy.
I have that discussion with her each visit and thus far we’ve decided to hold off on starting an anticoagulant drug like Eliquis. She has promised to record her ECG daily (using her Kardia Mobile ECG device) and report any onset of AF. If AF recurs we will have another discussion about Eliquis.
I spent several hours pouring over the original studies and more recent studies, reviews and meta-analyses and reached the following conclusions:
With the advent of the newer oral anticoagulants (NOACs) in the last decade which offer better stroke reduction and less bleeding than warfarin patient-physician discussions should be about taking a NOAC or not. Aspirin should not be considered as a lower risk/effective alternative as its benefits are minimal and bleeding risks similar to NOACs.
I told my patient no on the daily baby aspirin and from now on I will recommend stopping aspirin (assuming no other reason to be on it) to all my low risk AF patients.
The components of the stroke risk score- CHA2DS2-VASc = Congestive Heart failure, hypertension, Age ≥75 (doubled), Diabetes, Stroke (doubled), Vascular disease, Age 65–74, and Sex (female);
For those interested in a discussion on why females get a point in the risk score but a different cut-off for OAC therapy this is from the ESC guidelines:
Many risk factors contribute to the increased risk of stroke in patients with AF as expressed in the CHA2DS2-VASc score. The evidence for female sex as a risk factor has been assessed in many studies. Most studies support the finding that females with AF are at increased risk of stroke. One meta-analysis found a 1.31-fold (95% CI: 1.18–1.46) elevated risk of stroke in females with AF, with the risk appearing greatest for females ≥75 years of age (S4.1.1-35). Recent studies have suggested that female sex, in the absence of other AF risk factors (CHA2DS2-VASc score of 0 in males and 1 in females), carries a low stroke risk that is similar to males. The excess risk for females was especially evident among those with ≥2 non–sex-related stroke risk factors; thus, female sex is a risk modifier and is age dependent (S4.1.1-49). Adding female sex to the CHA2DS2-VASc score matters for age >65 years or ≥2 non–sex-related stroke risk factors
If you’re curious what constitutes a IIB recommendation it is described in the yellow box below My best summary is still “not a ringing endorsement”.
If you want to see the ESC guideline recommendations in detail
Since 1/3 of Americans die from atherosclerotic cardiovascular disease (ASCVD, mostly heart attacks and strokes) and dropping dead is often the first symptom of ASCVD it’s incredibly important to identify early, “subclinical” ASCVD and begin measures to reduce risk.
How early to begin that process is open to debate. The recent sudden death of the 41-year old son of a patient of mine, however, has reinforced to me how crucial it is to begin risk assessment and potential treatments as early as possible, especially in individuals with a strong family history of premature ASCVD.
We use standard risk factors like lipids, smoking, age, gender and diabetes to stratify individuals according to their 10 year risk of ASCVD (using this online risk calculator) but many apparent low risk individuals (often due to inherited familial risk) drop dead from ASCVD and many apparent high risk individuals have no subclinical ASCVD and don’t need preventive therapy.
Recent studies provide compelling support for the early utilization of cardiac imaging in to identify high risk individuals.
Heart attacks and most sudden cases of sudden death are due to rupture of atherosclerotic plaques. Thus, it makes sense to seek out such plaques, a process I call searching for subclinical atherosclerosis. There are a number of ways to search for sublinical plaques but the two most widely studied are carotid ultrasound screening and coronary artery calcification (CAC) measurement.
I’ve been utilizing CAC (also termed heart scan, coronary calcium score, or cardioscan) to help assess my patient’s risk of ASCVD for years although the procedure is not covered by insurance and until recently was not strongly endorsed by major guidelines. (For a complete description of the test and the risks/benefits see here). As I pointed out here, in November the new ACC/AHA guidelines finally embraced CAC for
adults 40 to 75 years of age without diabetes mellitus and with LDL-C levels ≥70 mg/dL- 189 mg/dL (≥1.8-4.9 mmol/L), at a 10-year ASCVD risk of ≥7.5% to 19.9%, if a decision about statin therapy is uncertain
Typically, if we have calculated (using the ASCVD risk estimator) a 10 year risk >7.5% we have a discussion with the patient about beginning drug treatment to reduce risk.
To inform the decision and help us “get off the fence” I usually recommend a CAC. To see how this works in a typical sixty something see my posts here and here.
Significant Of CAC Score
As the new ACC/AHA guidelines state:
If CAC is zero, treatment with statin therapy may be withheld or delayed, except in cigarette smokers, those with diabetes mellitus, and those with a strong family history of premature ASCVD.
A duo of studies from Walter Reed Army Hospital have provided more support for the value of the zero CAC for risk prediction and identifying who should get treatment for prevention of both heart attacks and strokes.
Over 10,00 subjects underwent CAC and were assessed for the primary outcomes of all-cause mortality, incident MI, stroke, and the combination of major adverse cardiovascular events (MACE), defined as stroke, MI, or cardiovascular death over an average 11.4 years
Patients were classified on the basis of the presence or absence of calcium and further subdivided into CAC score groups of 0, 1 to 100, 101 to 400, and >400
Patients without a zero CAC had a very low number of events , with a 1.0% rate of mortality and 2.7% rate of MACE over a 10-year period.
On the other hand subjects without any traditional risk factors (n = 6,208; mean age 43.8 years), the presence of any CAC (>0) was associated with a 1.7 fold increased risk of MACE after adjustment for traditional risk factors.
The red line of the >400 score individuals has a much higher risk of death, stroke and heart attack (myocardial infarction) than the blue (CAC 1-100) or the gray line of the zero CAC scorers.
Furthermore, when these investigators looked at outcomes in those individuals who received statins versus those who didn’t, the zeros didn’t benefit from statin therapy over the 10 year follow-up.
But there was a tremendous reduction in bad CV events in those with scores >100 who received statin (red line) versus those who did not (blue line).
Here’s the figure which encapsulates both the risk prediction power of the CAC (and the benefits of statin treatment restricted to those with >0 (blue lines)
Benefits of CAC Testing In The Young
So these new studies provide powerful data supporting the use of CAC in younger individuals to help us refine risk estimates and target the individual at high risk of MI and sudden death. It seems highly appropriate to consider CAC testing beginning at age 40 years as the AHA/ACC guidelines suggest.
But what about the individual who has a strong family history of premature CAD and is age say 35 or 39 years of age. Do we ignore advanced risk assessment? Very few individuals die in their 30s from ASCVD but I have a number of patients who suffered heart attacks in their forties. In addition, the earlier we can start risk modification the better as the process begins very early in life and accumulates over time.
The Coronary Artery Risk Development in Young Adults (CARDIA) Study published in 2017 has demonstrated the early development of nonzero CAC score in the youngish and the predictive value of the high CAC score for mid life ASCVD events. It was a prospective community-based study that recruited 5115 black and white participants aged 18 to 30 years from March 25, 1985, to June 7, 1986. The cohort has been under surveillance for 30 years, with CAC measured 15 (n = 3043), 20 (n = 3141), and 25 (n = 3189) years after recruitment. The mean follow-up period for incident events was 12.5 years, from the year 15 computed tomographic scan through August 31, 2014.
Any CAC in early adult life, even in those with very low scores, indicates significant risk of having and possibly dying of a myocardial infarction during the next decade beyond standard risk factors and identifies an individual at particularly elevated risk for coronary heart disease for whom aggressive prevention is likely warranted.
I read CAC scans every day and it is not uncommon to see a non-zero scores in individuals in their late 30s or early 40s.
The two sons of another one of my patients both in their late 50s with unremarkable risk factor profiles and both developing anginal type symptoms limiting their activities each underwent multi vessel stent procedures in the last month. If I had seen them 10 to 20 years ago we would have identified the subclinical atherosclerosis building up in their coronaries, started treatment and avoided the need for invasive, expensive procedures.
Other Risk-Enhancing Factors To Consider In The Young
The ACC/AHA guidelines list some “risk-enhancing factors” some of which I find useful.
Clearly family history of premature ASCVD is important but the devil is in the details. What relatives count? What was the event in the family member? If it was sudden death was an autopsy done?
What about nontraditional lipid/biomarkers? I consider an assessment of Lp(a) and some more sophisticated measurement of atherogenic dyslipidemia (apoB, LDL-P) and inflammation (CRP) essential.
Interestingly the guidelines include ABI (which I do not find helpful) but not carotid vascular screening which has frequently guided me to earlier therapy in youngish individuals with abnormal biomarkers or strong family history.
Vascular screening in young subjects may detect subclinical atherosclerosis as measured by thickening of the carotid wall (IMT) or early carotid plaque prior to the formation of calcium in the coronary arteries. Advanced IMT precedes the formation of soft plaque in arteries and only later is calcium deposited in the plaque.
It’s never too early to start thinking about your risk of cardiovascular disease. If heart disease runs in your family or you have any of the “risk-enhancing” factors listed above, consider a CAC, nontraditional lipid/biomarkers, or vascular screening to better determine were you stand and what you can do about it.
Included in my discussions with my patients with premature ASCVD is a strong recommendation to encourage their brothers, sisters and children to undergo a thoughtful assessment for ASCVD risk. With these new studies and the new ACC/AHA guideline recommendations if they are age 40-75 years there is ample support for making CAC a part of such assessment.
Hopefully very soon, CMS and the health insurance companies will begin reimbursement for CAC. As it currently stands, however, the 125$ you will spend for the test at my hospital is money well spent.
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.
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:
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.
Enrolled patients were predominantly male and white. No benefit was seen in women.
Higher rates of serious bleeding were noted in patients taking Vascepa
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.
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.
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.
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
-126.96.36.199. 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 (S188.8.131.52-1–S184.108.40.206-8). 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 (S220.127.116.11-9–S18.104.22.168-12). 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 (S22.214.171.124-13). With increasing age, 10- year risk accompanying CAC scores of 1 to 99 rises, usually crossing the 7.5% threshold in later middle age (S126.96.36.199-13). When the CAC score is zero, some investigators favor remeasurement of CAC after 5 to 10 years (S188.8.131.52-14–S184.108.40.206-16). 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 (S220.127.116.11-17). A prospective randomized study of CAC scoring showed improved risk factor modification without an increase in downstream medical testing or cost (S18.104.22.168-18). 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 (S22.214.171.124- 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
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
“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.
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.
The two recent articles (mentioned in this post) supporting full fat dairy are:
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
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 Medicinefurther 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 month) as 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.
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.
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.
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
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
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
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
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)
It is the strongest single inherited (monogenetic) risk factor for the early development of coronary artery disease, heart attacks and strokes.
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.
Depending on the cut-off used up to one in five individuals may have elevated Lp(a)
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.
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.
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.
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.
For those patients seeking more detailed information and references I recommend Dr. Siggurdson’s excellent post on Lp(a)
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)
This 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.
Your 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, Kevin 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.
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.
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.
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.
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.