Category Archives: Cardiac Medications

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

Are Physicians Influenced By Pharmaceutical Gifts?

The Skeptical Cardiologist stopped giving talks for pharmaceutical companies 5 years ago and stopped accepting lunches from pharmaceutical reps because he wanted to be certain that he was not being influenced by them in his writing or patient care.

I made an exception 6 months ago and consumed panang curry provided by a pharmaceutical representative who was promoting the blood thinner Pradaxa.

He enthusiastically extolled the virtues of Pradaxa throughout the lunch and made some excellent points supporting the use of the drug. Shortly thereafter, when I was considering which of the newer blood thinners to prescribe for a patient , Pradaxa was foremost in my mind.

The scientific data that Boehringer Ingelheim wanted me to be aware of entered the crowded marketplace of ideas in my head that day but I prefer the data that enters my consciousness come from unbiased sources.

A new study from Georgetown University, published in PLOS One provides support for physicians eschewing pharmaceutical gifts.

The authors point out in their introduction that gifts are important:

Gifts, no matter their size, have a powerful effect on human relationships. Reciprocity is a strong guiding principle of human interaction. Even gifts of small value, such as “modest” industry-sponsored lunches, may foster a subconscious obligation to reciprocate through changes in prescribing practices. DeJong et al has shown that a meal with a value of less than $20 can increase the prescribing of branded statins, beta-blockers, ACE inhibitors, and antidepressants.

The study found:

Physicians who received small gifts (less than $500 annually) had more expensive claims ($114 vs. $85) and more branded claims (30.3% vs. 25.7%) than physicians who received no gifts. Those receiving large gifts (greater than $500 annually) had the highest average costs per claim ($189) and branded claims (39.9%) than other groups. All differences were statistically significant (p<0.05).

The conclusions of the study:

Gifts from pharmaceutical companies are associated with more prescriptions per patient, more costly prescriptions, and a higher proportion of branded prescriptions with variation across specialties. Gifts of any size had an effect and larger gifts elicited a larger impact on prescribing behaviors. Our study confirms and expands on previous work showing that industry gifts are associated with more expensive prescriptions and more branded prescriptions. Industry gifts influence prescribing behavior, may have adverse public health implications, and should be banned

Michael Joyce has written a detailed and insightful analysis of this paper at the excellent website, HealthNewsReview.org.

He points out the limitations of this and all observational studies:

Although the study cannot definitively establish cause-and-effect between a provider receiving such gifts and any subsequent upturn in their prescribing, it does make a significant contribution to a growing body of literature documenting how drug company largesse is clearly linked — either consciously or otherwise — to the way in which health care providers prescribe.

And the article quotes Daniel Goldberg, an expert on bioethics:

“First, in situations when the evidence is imperfect, and the decisions are subtle, as is so often true in medicine. In these ambiguous situations the evidence clearly suggests that gifts can sway doctors in one direction, even if there’s no evidence to support that as the best decision. Second, it frames decisions in pharmaceutical terms, even when there may be other options — proven to be better — that have nothing to do with drugs.

Drugs are just one tool. But we have ‘pharmaceuticalized’ health care to a point where many patients are conditioned to equate health with access to drugs.”

Since I consumed the panang curry, I’ve gone back to bringing in my own lunch. Thus, my lunch/breakfast typically consists of Trader’s Point full fat plain yogurt with lots of blueberries and raspberries, and perhaps some ground up flaxseed and/or almonds (although today I’ll be bringing in leftover-meatloaf and roasted root vegetables.)

It’s not as tantalizing as the curry, but it leaves my crowded brain free to ponder the multitude of unbiased data from scientific papers, rather than the talking points a pharmaceutical representative would prefer I ponder.

The end result, I hope, is unbiased blogging and prescribing-better information for readers and better care for patients.

-ACP

 

Study Shows EpiPens Effective Up to 50 Months After Expiration Date

The skeptical cardiologist recently revealed that he had been relying on an EpiPen that expired in 2011. Apparently, I was not entirely wrong to keep that old EpiPen around.

A research letter published in the Annals of Internal Medicine found that EpiPens:

 did lose potency over time. Even 50 months past expiration, however, the EpiPens retained 84 percent of epinephrine concentrations – enough to prevent anaphylactic shock,.

Per Reuters based on an email from Julie Knell, Mylan’s senior director for global product communications:

The expiration dates stamped on EpiPens reflect “the final day, based on quality control tests, that a product has been determined to be safe and effective when stored under the conditions stated in the package insert,” Knell said. “Given the life-threatening nature of anaphylaxis, patients are encouraged to refill their EpiPen Auto-Injector upon expiration, approximately every 12 to 18 months.”

Pharmacists indicate they may not get EpiPens until 6 months after manufacture meaning that patients must replace them annually. Extending the shelf-life to 24 months therefore would halve the annual cost of the devices.

-ACP

EpiPen Comeuppance: Cheaper Alternatives and A World-Wide Recall

The skeptical cardiologist described his own exciting episode of EpiPen usage while discussing the outrageously increased  costs of the medication in a post last year., writing:

Although the active ingredient, epinephrine, is generic and cheap, and the basic delivery system has been around for decades,  Mylan, the company that purchased the rights to EpiPen in 2007 has increased its price from 57$ per injector to 600$ for 2 injectors.

Lack of generic competition to the EpiPen  is the primary reason that the price could be raised so much and also explains in many circumstances why drug costs are high in the US.

Two developments since then hopefully have cut into Mylan’s unseemly profits from the product: cheaper alternatives and cases of EpiPen failure.

As Fortune noted

Public and Congressional outrage not only forced Mylan to pay a $465 million settlement and launch a cheaper, generic version of the injection device, but it also spurred rivals and regulators to speed competing epinephrine injectors to market to lower costs.

EpiPen Failures and Recall

In April, two cases of EpiPen failures were reported and Mylan initiated a world-wide recall of EpiPen’s manufactured during a certain time period.

This recall announcement spurred me to examine the EpiPens I had, including one I carry in my work satchel and one I have at home.

To see if you have an EpiPen that should be recalled check the black box on the side of the injector for the Lot # and then go to this link on the Mylan webpage to determine if your EpiPen has been recalled. Follow the directions for getting a voucher for a free new one.

If you’re like me, you haven’t actually checked the expiration date for years and will be shocked to find that it was 6 years ago!

Generic AdrenaClick: A Cheaper Epinephrine Auto-injector (EAI)

I called my pharmacist to find out my options for replacing the EpiPen and discovered that my insurance company (UMR) did not cover EpiPens at all. I had already researched alternatives and discovered that Lineage Therapeutics makes one called AdrenaClick and they also are now offering a generic version of AdrenaClick which, with a coupon that is offered at their website, ends up costing 10$.

Fortunately, for me the website informed me that this product is my “GO-TO-CHOICE”:

*Impax authorized generic of Adrenaclick® (epinephrine injection, USP auto-injector), also called epinephrine auto-injector or EAI. Impax EAI contains the same active medicine as EpiPen®. Impax EAI has numbered and color-coded instructions, designed for single-dose use by patients and caregivers. Impax EAI is a low-cost choice that is FDA approved… it’s the GO-TO-CHOICE for affordable, emergency treatment of allergic reactions (Type I) including anaphylaxis.

Consumer Reports has recommended this product. You need to have your doctor write the prescription for “epinephrine auto-injector.” and not for Epipen to insure proper substitution.

The technique for auto-injection is only slightly different from that of an EpiPen and you can view it here.

Shift To The Epi Auto-injector and Stick It To Mylan

It looks like I’m not the only one making a shift to a generic EAI.

This chart shows the dramatic rise that occurred in alternative prescriptions up to February, 2017

 

Mylan stock meanwhile, which dropped precipitously after adverse publicity (and my post?) in the fall of 2016 had been making a recovery but with the failed injections and the recall it is in free-fall again.

So, let’s all stick it to Mylan and when you happen to check your EpiPen and find that it expired 6 years ago replace it with something cheaper.

lancinatingly yours,

-ACP

p.s. I may never get around to writing about a useless drug called Yosprala that is being heavily marketed to physicians. The drug consists of two drugs which are cheap and available over the counter: aspirin and omeprazole (a proton pump inhibitor that reduces stomach acid and therefore ulcers.)

Yosprala sells for 150$/month. You can get either a baby aspirin (81 mg) or a full aspirin (325 mg) for pennies a day and 40 mg omeprazole (prilosec) for 46 cents per day.

Why would you pay 30 times as much for the combination?

If your doctor prescribes this stuff ask him if he has had any lunches with the Aralez pharmaceutical rep.

Has The Digoxin Death Knell Sounded: Farewell To Foxglove?

The lovely but deadly foxglove plant encountered randomly on a hike through glorious Wales on a dreary, rainy day.

The skeptical cardiologist is fascinated by the cardiac drug digoxin and the plant from which it is derived, the foxglove.

I wrote about “foxglove equipoise” in a previous post, touching on the contributions of William Withering in the 1700s, to understanding the toxicity and therapeutic benefits of the foxglove, and more recent concerns that digoxin increases mortality in patients with heart failure.

At the American College of Cardiology Scientific Sessions in Washington, D.C. yesterday, a paper showing higher mortality for patients on digoxin may be the final nail in the foxglove coffin.

Despite lack of evidence for its safety in the treatment of atrial fibrillation from randomized trials, digoxin is used in 30% of patients with atrial fibrillation (AF) worldwide, and current AF guidelines recommend it for rate control in patients with AF (with and without heart failure).

The investigators used data from the ARISTOTLE study of apixiban versus warfarin for their analysis.

They looked at mortality in patients taking or not taking digoxin at baseline, using a Cox model with propensity weighting, which included demographic features as well as biomarkers and digoxin levels at baseline. Major findings:

-In patients already taking digoxin, mortality was not higher in digoxin users, however, the risk of death was related to dig levels: for every 0.5 ng/ml increase in dig level, the risk of death rose by 19 percent and if dig level was >1.2 ng/ml the death rate increased by 56 percent. 

Patients not taking digoxin before the trial who began taking it over the course of the study had a 78 percent increase in the risk of death from any cause and a four-fold increased risk of sudden death after starting digoxin use.  Most sudden deaths occurred within six months after digoxin was started.

Risk of death with initiation of digoxin was increased in patients with and without heart failure.

The use of foxglove to treat dropsy is a fascinating and instructive chapter in the history of medicine.

This study added to prior systematic reviews suggests that it is time to end the use of digitalis and close the chapter.

William Withering might turn over in his grave but at least we won’t be sending afib patients to join him prematurely!

Dropsily Yours,

-ACP

 

Are You On The Fence About Taking A Statin Drug?

The father of the eternal fiancee’ of the skeptical cardiologist (FOEFOSC, let’s call him “Geo”) is a typical 61 year old white male. A year ago his primary care physician informed him that he needed to start taking a statin drug because his cholesterol was high. The note accompanying this recommendation also stated “work harder on diet and exercise to get LDL<130.”  No particulars on how to change his current diet and exercise program were provided.

Neither of Geo’s parents and none of his siblings have had heart problems at an early age and Geo is very active without any symptoms. His diet is reasonably free of processed food and added sugar, he is not overweight and his blood pressures are fine. Due to concern about side effects he had read about on the internet and because he doesn’t like taking medications , Geo balked at taking the recommended statin,

Reluctance to start a new and likely life-long drug is understandable especially when combined with a constant stream of internet-based bashing of statins.

My advice was sought and I suggested a few things that would be helpful in making a more informed decision:

-Calculate Geo’s 10 year risk of heart attack and stroke using the ACC ASCVD Risk estimator app.

-Assess for early or advanced build-up of atherosclerotic or fatty plaque in the carotid arteries (vascular ultrasound) and coronary arteries (coronary calcium scan).

As I’ve pointed out before (here), the vast majority of men over the age of 60 move into a 10 year risk category >7.5%, no matter how great their lifestyle is, and Geo was no exception with a risk of 8.4%. His total cholesterol was 249, LDL (bad) 154, HDL (good) 72 and triglycerides 116.

The vascular ultrasound showed below normal carotid thickness and no plaque and his coronary calcium score was 18,  putting him at the 63rd  percentile. This is slightly higher than average white men his age.

When Geo presented these findings to his PCP, he seemed unaware of the ASCVD risk estimator (recommended by AHA/ACC guidelines first published in 2013), which no longer suggests LDL levels as goals. His PCP also seemed miffed that he had gotten the coronary calcium scan. Geo felt like the PCP’s attitude was “shut up and do what I tell you.”

Geo’s PCP’s approach exemplifies a not-uncommon traditional doctor-patient relationship, but a better approach is shared decision-making (see here). Geo, like many patients, welcomes more information on the risks and benefits of any recommended treatment so that he can participate in deciding the best course of action.

I steer patients who want more complete information towards my  evidence-based blog posts on statins (see here for discussion on statin side effects and here for statin benefits beyond cholesterol lowering.)

By giving patients more information on the risks, side effects, and benefits of the statin drugs along with a better understanding of their overall risk of heart disease and stroke, we can hopefully move more patients “off the fence” and onto the most appropriate treatment.

Stay tuned to find out what The Skeptical Cardiologist Recommended for Geo.

Decisively Yours

-ACP

For more discussion on the value of coronary artery calcification (CAC) and the value of statin in lower risk patients see this recent paper entitled “Refining Statin Prescribing in Lower-Risk Individuals: Informing Risk/Benefit Decisions”(PDF refining-statin-prescribing-in-lower-risk-individuals-informing-riskbenefit-decisions)

If you’d like to read the recently published recommendations of the US Preventive Services Task Force on statins for primary prevention of cardiovascular disease see here. Importantly this panel of unbiased experts concluded that statin therapy significantly reduced overall mortality and cardiovascular mortality. In addition, the review found no increased risk of diabetes overall with statin therapy. The only trial that identified an increased risk was using high intensity statin therapy (Crestor (rosuvastatin) >20 mg).

And,  since the internet is jammed with people who believe statins robbed them of their brain power, I would advise noting that the writers concluded  “These findings are consistent with those from a recent systematic review of randomized trials and observational studies that found no adverse associations of statins with incidence of Alzheimer disease, dementia, or decreased scores on tests of cognitive performance.”

 

 

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

 

Withering Away in Wales

The skeptical cardiologist was born in Wrexham, North Wales, not too far from the northern area in Wales known as Snowdonia, the ancestral lands of the great Princes of Wales.

I’ve been back to this wonderful area several times in the last dozen years, entranced by its beauty and connection with my ancestor, Prince Llewelyn the Great.

Most recently I stayed in Beddgelert, a small village nestled at the base of Mount Snowdon, which , according to (possibly tourism-inspired) legend, is named after the grave of Gelert, the faithful hound of Prince Llewelyn.

A brief hike along the gurgling Glaslyn river takes you to a stone monument with these words inscribed:

IMG_4547
Two Pearson children show their appreciation of Gelert’s heroic behavior. Note the purplish flower on the long green stalk in the background, next to the stone wall-FOXGLOVE!

“In the 13th century Llewelyn, prince of North Wales, had a palace at Beddgelert. One day he went hunting without Gelert, ‘The Faithful Hound’, who was unaccountably absent.                                                  On Llewelyn’s return the truant, stained and smeared with blood, joyfully sprang to meet his master. The prince alarmed hastened to find his son, and saw the infant’s cot empty, the bedclothes and floor covered with blood.                      The frantic father plunged his sword into the hound’s side, thinking it had killed his heir. The dog’s dying yell was answered by a child’s cry. Llewelyn searched and discovered his boy unharmed, but nearby lay the body of a mighty wolf which Gelert had slain.

The prince filled with remorse is said never to have smiled again. He buried Gelert here”.

IMG_0007While lingering in the little stone wall enclosure within which a statue of the faithful Gelert stood I espied a plant that looked like digitalis purpurea, more commonly known as foxglove.

Moving closer, I realized that I had indeed come face to face with a wildly growing foxglove,  the plant that William Withering had utilized to treat patients with dropsy in the late -1700s.

I was understandably ecstatic as I was  on a sort of mission to observe foxglove in its native environs. I had expected to view the medicinal plant in Shropshire where William Withering was born and where he had encountered “the old woman of Shropshire” who first inspired him to use foxglove for dropsy.

This unexpected foxglove experience seemed like a serendipitous harbinger of wonderful Witheringesque experiences to come.

Sure enough as we left the fog-enshrouded mountains of Snowdonia and drove on the left side of narrow, winding Welsh roads toward Shropshire we spotted a multiple large patches of wildly growing foxglove in a nearby meadow.

dpeating foxgloveAlthough my children were eager to taste the foxglove and see if the inotropic properties of the digitalis within would make their hearts beat stronger and make them more powerful, I restrained them, for Withering’s writings and subsequent years of clinical experience with digitalis tell us that the therapeutic window is narrow and toxicity manifested by nausea and vomiting common.

Should I Take Aspirin To Prevent Stroke or Heart Attack?

 

Aspirin is a unique drug, the prototypical  two-edged sword of pharmaceuticals.  It 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 statement recommending 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.

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 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.