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.
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.
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.
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.
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!
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:
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.
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.
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.”
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.
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:
“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”.
While 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.
Although 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.
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 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.
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.