Category Archives: Cardiac Medications

My Top Four Practice-Changing Presentations From the ACC 2019 Meeting: From Alcohol To Aspirin

The ACC meetings in New Orleans have wrapped up and I must stop letting the good times roll.

In the areas I paid attention to I found these four presentations the most important:

1. After the historic back to back presentations of the Partner 3 and Evolut trials it is clear that catheter-based aortic valve replacement (TAVR) should be the preferred approach to most patients with severe symptomatic aortic stenosis.

Both TAVR valves (the baloon-expanded Edwards and the self-expanding Medtronic) proved superior to surgical AVR in terms of one year clinical outcomes.

2. The Alcohol-AF Trial. It is well known that binge alcohol consumption (holiday heart) can trigger atrial fibrillation (AF) and that observational studies show a higher incident of AF with higher amounts of alcohol consumption.

This trial was the first ever randomized controlled trial of alcohol abstinence in moderate drinkers with paroxysmal AF (minimum 2 episodes in the last 6 months) or persistent AF requiring cardioversion.

Participants consumed >/= 10 standard drinks per week and were randomized to abstinence or usual consumption.

They underwent comprehensive rhythm monitoring with implantable loop recorders or existing pacemakers and twice daily AliveCor monitoring for 6 months.

Abstinence prolonged AF-free survival by 37% (118 vs 86 days) and lowered the AF burden from 8.2% to 5.6%

AF related hospitalizations occurred in 9% of abstinence patients versus 20% of controls

Those in the abstinence arm also experienced improved symptom severity, weight loss and BP control.

This trial gives me precise numbers to present to my AF patients to show them how important eliminating alcohol consumption is if they want to have less AF episodes.

It further emphasizes the point that lifestyle changes (including weight loss, exercise and stress-reduction) can dramatically reduce the incidence of atrial fibrillation.

3. AUGUSTUS. This trial looked at two hugely important questions in patients who have both AF and recent acute coronary syndrome or PCI/stent. The trial was simultaneously published in the New England Journal of Medicine. The questions were:

Apixaban (Eliquis, one of the four newer oral anticoagulants (NOAC)) versus warfarin for patients with AF: which is safer for prevention of stroke related to AF?

Triple therapy with  low dose aspirin and clopidogrel plus warfarin/NOAC versus clopidogrel plus warfarin/NOAC: which is safer in preventing stent thrombosis without causing excess bleeding in patients with AF and recent stent?

Briefly, they found:

The NOAC apixaban patients compared to warfarin had a 31% reduction in bleeding and hospitalization. No difference in ischemic events.

Adding aspirin  increased bleeding by 89%. There was no difference in  ischemic events. (Major or clinically relevant nonmajor bleeding was noted in 10.5% of the patients receiving apixaban, as compared with 14.7% of those receiving a vitamin K antagonist (hazard ratio, 0.69; 95% confidence interval [CI], 0.58 to 0.81; P<0.001 for both noninferiority and superiority), and in 16.1% of the patients receiving aspirin, as compared with 9.0% of those receiving placebo (hazard ratio, 1.89; 95% CI, 1.59 to 2.24; P<0.001).)

This means that the dreaded “triple therapy”  after PCI in patients with AF with its huge bleeding risks no longer is needed.

It also further emphasizes that NOACs should be preferred over warfarin in most patients with AF.

The combination of choice now should be a NOAC like apixaban plus clopidogrel.

4. REDUCE-IT provided further evidence that icosapent ethyl (Vascepa) significantly reduces major cardiovascular events in patients with establshed CV disease on maximally tolerated statin therapy.

The results of the pirmary end point from the REDUCE-IT were presented at the AHA meeting last year and they were very persuasive. At the ACC, Deepak Bhatt presented data on reduction of total ischemic events from the study and they were equally impressive. Adding the pharmaceutical grade esterified form of EPA at 2 grams BID reduced first, second, third and fourth ischemic events in this high risk population.

The benefit was noted on all terciles of baseline triglyceride levels. Thus, the lowest tercile of 81 to 190 mg/dl benefitted as well as the highest tercile (250 to 1401).

Although I dread the costs, it’s time to start discussing adding Vascepa on to statin therapy in high risk ASCVD patients who have trigs>100 .

As I wrote previously I didn’t learn anything from the much ballyhooed and highly anticipated Apple Heart Study . It’s entirely possible more participants were harmed than helped by this study.

Philomathically Yours,

-ACP

Is there a Yelp for Medications and should you be using it?

The skeptical cardiologist recently prescribed ezetimibe to a patient who was leery of taking statin drugs for her elevated cholesterol. In the past she had taken red yeast rice in the belief that this was a safe and natural way to lower her cholesterol. I told her that I had looked into and researched red yeast rice (and wrote about it here), and that it was neither safe nor effective.

When I saw her back at our next office visit, she informed me that she had done her own research. She had gone on the internet and Googled ezetimibe and based on its “reviews” she felt it was an unsafe and dangerous drug.

It occurred to me at that point that patients like Ms X may actually believe that they can get reliable information on drug side effects and efficacy by going to a website where patients leave reviews on drugs they have taken.

Yelp For Medications

Such sites would be the equivalent of Yelp, which the wife of the skeptical cardiologist utilizes extensively to determine which restaurants we should patronize.

Lo and behold, if one Googles “reviews Zetia” a whole host of websites pop up offering you the opinions of random individuals on the drug.

On Everday Health Zetia gets 2 stars from 34 reviews with the most recent review being quite negative;

I hadRated Zetia for Rheumatoid Arthritis Report BEWARE. My husband took Zetia along with stantin, Crestor. Within a week, his leg muscles inflamed and shut down his kidneys and liver. He has been in the hospital for over a month and his condition has not improved. He’s on dialysis and can not walk. He is an alcoholic and his liver failed with Zetia.

The 234 reviews of Zetia on WebMD (another site I don’t recommend) are also pretty negative. Here’s a typical one;

Low dose of Zetia ….After just first days had severe diarrhea, halfed the dose. After a month I started seeing flashes in my right eye. Lots of eye fatigue, now a lot of ‘floaters’ in my right eye. Got checked by eye doctor to make sure it wasn’t optical nerve damage. Scarey. Coincidence? Don’t think so. 

Limitations of The Yelp Concept In Assessing Medications

I empathize with and totally respect my patient’s desire to do her own independent research on the potential side effects of a drug that she will be putting in her body.

However, the Yelp approach just does not work well for medications.

There are three problems with relying on these kinds of patient-reported medication side effects.

The first is that the patients who leave comments on these sites are not representative of the overall pool of patients receiving the drug. Patients who feel they have been harmed in some significant way are much more likely to be motivated to spend the time recording what happened to them than are the individuals who felt fine after taking the drug.

There were 4 million prescriptions for ezetimibe written in 2015 and the number of patients leaving comments on these patient-review websites at most number in the hundreds. Thus, 99.9% of those taking ezetimibe are being silent, most likely because they are doing fine with the drug.

Secondly, most of the side effects reported by patients after taking ezetimibe occur at about the same frequency in those who take a placebo.

Although the package insert for ezetimibe lists various “common” side effects of the drug (such as diarrhea and upper respiratory infection), this table from the same package insert shows that such ailments are about as common in the group taking placebo.

The manufacturer, following FDA guidelines, reports out adverse reactions that are more common than 2% and numerically greater than placebo, but these are not necessarily significant differences.

Thus, we see that 4.1% of patients taking Zetia had diarrhea, but also that 3.7% of patients taking placebo had diarrhea.

If you take any group of several thousand individuals and follow them for a couple of months, probably 4% will get diarrhea whether or not they are taking ezetimibe.

The Nocebo Effect

Finally, we have to take into account the nocebo effect. The opposite of the placebo effect, in which inert substances make patients feel better, the nocebo effect makes patients who believe a drug will have side effects much more likely to experience those side effects.

The nocebo effect is quite common in patients who have read very negative comments on the internet about statin side effects. It is clear to me that this statin-related nocebo effect has also influenced patients taking non-statin cholesterol lowering medications like ezetimibe.

This is such an important factor in how patient’s tolerate ezetimibe that I spend considerable time during office visits emphasizing that ezetimibe works in a totally different way than statins, and is not associated with muscle aches/myalgias.

Alas, my patient has chosen to rely on the Yelp approach to deciding which medications to take. I’ve given her the best information I could on the safety and efficacy of ezetimibe based on my years of prescribing it and studying it. At this point it is her decision to make, and I accept it and we move forward managing her cardiovascular disease with the other tools in my toolkit.

Unlike an inaccurate restaurant review, however, a single individual describing inaccurately horrific side effects of a medication has the potential to steer thousands of patients away from potentially life-saving therapy.

Skeptically Yours,

-ACP

How Important Are Grapefruit (OR CBD Oil)-drug Interactions? David Bailey vs The Florida Dept. of Citrus

Previously, the skeptical cardiologist described a patient  with atrial fibrillation who was taking the blood thinner apixaban (Eliquis ) and developed a nose bleed after consuming a large amount of grapefruit (see here.)

In researching the whole subject of grapefruit-drug interactions I came across a fascinating intellectual battle between David Bailey, the researcher who first identified a significant grapefruit-drug interaction, and clinicians and researchers, some of whom are supported by the Florida Citrus Board, who feel this interaction is not significant.

What Does The Internet Tell Us?

It’s always interesting to see what patients doing a Google search will see on important medical topics. When I Googled  “grapefruit Eliquis interaction” I saw the following:

Screen Shot 2018-06-22 at 9.56.04 PM

The first item is an ad from the company that makes Eliquis which takes you to their patient-oriented Eliquis site and immediately presents you with important patient safety information. Nowhere on the site is the word grapefruit listed (as of July, 2018).

The second item is what Google calls a snippet and which they will present to you as what they think is the best answer to your Google search question. In this case the snippet  (and the first 4 hits) is lifted from Web MD an absolutely unreliable source of information (see my post on entitled Web Md:Purveyor of bad health information and snake oil) but one which Google (and thus millions of unsuspecting Googlers) relies on for answers to medical questions . Web MD advises you to avoid grapefruit if you’re taking eliquis.

Close inspection of the WebMD article proffering this advice reveals the sole reference that actually bears on this topic: (Bailey et al , 2012 , CMAJ).

The main author of this paper (which has  the oddly phrased title Grapefruit–medication interactions: Forbidden fruit or avoidable consequences? ) is David Bailey.

David Bailey: Rapid Runner and Grapefruit Alarmist

David Bailey may be  better  known as the first Canadian to run a mile in under 4 minutes. His Wikipedia entry spends equal time on his running career and on his major claim to fame: grapefruit drug interactions (GDI).

Bailey serendipitously discovered that grapefruit increased levels of the antihypertensive drug felodipine in his own body in 1987,  information which was pretty much ignored until he published a research paper in the Lancet in 1991 showing a doubling of felodipine levels in 6 volunteers who consumed grapefruit.

Since then studies have shown that grapefruit juice  acts by reducing presystemic felodipine metabolism through selective post-translational down regulation of cytochrome P450 3A4 (CYP3A4) expression in the intestinal wall.

Bailey has taken the grapefruit (and Seville orange) ball and run with it. His publications emphasize the broad scope and potential dangers of multiple grapefruit-drug interactions.  A 2012 Bailey paper  lists 85 drugs with the potential to interact with grapefruit juice including, you guessed it, apixaban.

Despite these potential interactions the actual number of clinically significant interactions or harm reported is minuscule. This has not deterred Bailey from emphasizing the importance of the interaction he discovered.

He is  quoted in a 2012 NY Times article as saying:

“The bottom line is that even if the frequency is low, the consequences can be dire,” he said. “Why do we have to have a body count before we make changes?”

“For 43 of the 85 drugs now on the list, consumption with grapefruit can be life-threatening, “

Articles, like the NY Times article typically  buy into Bailey’s fear-mongering and spend multiple paragraphs describing a single case report suggesting that ingestion of grapefruit juice was responsible for a dangerous  interaction but such cases are rare and strong evidence that grapefruit juice was responsible is not present.

What Can We Learn From The Florida Department of Citrus?

In fact, in a letter to the editor in response to Bailey’s 2012 review, two researchers point out that their is little solid evidence to suggest that the grapefruit-drug interactions are important

We know of no validated evidence that coadministration of grapefruit juice with a drug has caused a dangerous interaction, resulting in serious adverse effects or actual harm to a patient’s health. We point readers to 2 extensive review articles on grapefruit juice–drug interactions that have appeared in peer-reviewed medical literature.2,3 These articles provide a review of primary research literature, a compilation of the extent of interactions with specific drugs, and an evaluation of their clinical importance; however, neither of these publications is cited in the CMAJ article.

Whereas David Bailey has a bias to promote and exaggerate an interaction that is his claim to scientific fame most of the research and reviews that counter his claims come from researchers who are likely heavily biased to minimize the importance of the interaction: they are funded by the Florida Department of Citrus.

Are We Missing Important Grapefruit Medication Interactions?

David Bailey would like  us to believe that the GFDI he identified in 1998 is hugely important. If only doctors would spend more time investigating the grapefruit consumption of their patients we would realize this.  He writes

But how big a problem are such interactions? Unless health care professionals are aware of the possibility that the adverse event they are seeing might have an origin in the recent addition of grapefruit to the patient’s diet, it is very unlikely that they will investigate it. In addition, the patient may not volunteer this information. Thus, we contend that there remains a lack of knowledge about this interaction in the general health care community. Consequently, current data are not available to provide an absolute or even approximate number representing the true incidence of grapefruit–drug interactions in routine practiceThe chemicals in grapefruit involved in this interaction are the furanocoumarins.7

Bailey, goes on to warn us that all forms of grapefruit consumption can lead to dangerous interactions and other citrus fruits are to be feared as well

Because these chemicals are innate to grapefruit, all forms of the fruit (freshly squeezed juice, frozen concentrate and whole fruit) have the potential to reduce the activity of CYP3A4. One whole grapefruit or 200 mL of grapefruit juice is sufficient to cause clinically relevant increased systemic drug concentration and subsequent adverse effects.11,12 Seville oranges, (often used in marmalades), limes and pomelos also produce this interaction.1315 Varieties of sweet orange, such as navel or valencia, do not contain furanocoumarins and do not produce this interaction.2

You can follow his references but they are not to patients who were harmed by grapefruit-drug interactions. Indeed, I am unaware of any of my patients reporting such harm until my patient with the nose bleed. I tend to agree with this unbiased editorial from BMJ in 2013

In our experience, and in that of our experienced colleagues, we have yet to come across clinically meaningful interactions of drugs and GFJ. This is despite our day to day experience of managing patients on statins, calcium channel antagonists, anti-platelet agents and anti-arrhythmics, which covers over 10,000 patients in the last 10 years alone. Likewise, there is little formal evidence of an impact, even from large scale clinical trials, with adjudicated and well documented endpoints.

After considerable research and communication with Pfizer, the maker of Eliquis, I ended up agreeing with Pfizer’s conclusion that the grapefruit-Eliquis interaction was unlikely to be significant:

When consumed in usual dietary volumes, grapefruit juice is considered a moderate inhibitor of CYP3A4. Therefore a dose adjustment of apixaban is not expected to be required.

CBD Oil, Grapefruit And Drug Interactions

I was reminded of the grapefruit-drug interaction in the last few weeks as several of my patients have started using CBD oil for various problems and have asked if it is safe to use with their cardiac medications.

I haven’t fully researched the CBD oil-drug interaction but the top Google search (“grapefruit and CBD oil”) result (from CBD school)  states the following:

CBD interacts with other medications in your body in the same way as grapefruit, only even stronger.

However, the site that CBD school references (Project CBD) is not that definitive about grapefruit-drug interactions being a guide to CBD-grapefruit interactions.

And a recent scholarly article on the topic (see here) concludes

The drug-drug interactions between cannabinoids and various drugs at the CYP level are reported, but their clinical relevance remains unclear.

Which sounds very similar to where we are at with grapefruit-drug interactions in general.


I had my patient perform an experiment to see if the grapefruit actually caused her nose bleed. She repeated her consumption of large amounts of grapefruit and had no nosebleed this time.

Nonepistaxisly Yours,

-ACP

Is Pitavastatin (Livalo) A Better Statin For You?

The skeptical cardiologist recognizes that perhaps 10% of patients he starts on a statin drug will develop symptoms that are felt to be due to the drug.

Most often the symptom is myalgia-muscle ache.

But other symptoms may develop after the patient starts the drug and given widespread statin fear-mongering on the internet it is common for these symptoms to be attributed to the statin.

Recently a reader left comments on my post on statins and memory problems describing in detail what appears to be a statin side effect:

My doctor had me on a daily 40mg Lipitor. After about 1 month, I noticed that my short term memory was very bad*. (Not a nocebo effect… I had no idea at the time that statins were linked to memory effects.) I did an experiment on myself. I suspected that my memory problems were the result of the statin. (Nothing else seemed to be different besides the fact that I had started taking Lipitor the previous month.) After 2 weeks off of Lipitor, my memory problems went away. Whew. I put myself back on Lipitor (I didn’t want to die of a heart attack, and my “experiment” could have been a victim of confirmation bias + 100 other faults.) After about a month, crappy short term memory returned. Took myself off Lipitor again. AGAIN, after about 2 weeks, by memory was fine again.
Perhaps my experiment wasn’t scientific. Just one subject (me). 100% anecdotal. Perhaps statins are good for your heart. However, I don’t know about you, but I program computers for a living. Try doing that with crappy short term memory. Hint: you can’t do it.

I’ve outlined my approach to these potential statin associated symptoms (PSAS) previously (see here) and if a patient has resolution of the PSAS we typically try another statin to see if the PSAS recurs.

For my reader, it would make sense to try a statin like rosuvastatin or pitavastatin that is hydrophilic and therefore doesn’t cross the blood-brain barrier and enter the brain.

For the more common myalgias I typically try rosuvastatin at lower dosage. If symptoms recur on rosuvastatin I try pitavastatin.

Pitavastatin (Livalo)

Pitavastatin (Livalo) is the seventh statin. It is minimally affected by the cytochrome P450 system (meaning less drug-drug interactions),  water soluble (so it doesn’t enter the brain,) and does not lower Co-enzyme Q10.  These special biochemical characteristics raise the possibility that  among patients who have not been able to tolerate other statins it might be both usable and efficacious.

It has been used in Japan since 2003 and was approved by the FDA for US use in 2010. The Medical Letter was pretty negative about it in 2010 and feels the same way about the recently approved zypitamag (pitavastatin magnesium.)

The Medical Letter’s review of pitavastatin calcium concluded that recommended doses of the drug had not been shown to decrease LDL-C more than other statins with longer safety records and there was no good reason to use it. That conclusion applies to pitavastatin magnesium as well.

Tom Dayspring, the “national treasure” and lipidologist disputes this and has written of the Medical Letter conclusions

Any statin that has been tested in an outcome trial has been successful and there is no reason why pitavastatin would not also reduce events. Most providers used every statin for years before there were outcomes! Pitavastatin was as successful in
regressing plaque volume as was atorvastatin in an IVUS trial called JAPAN-ACS ((J Am Coll Cardiol 2009;54:293–302). The claim regarding LDL lowering is erroneous as pitavastatin is actually more efficacious than fluvastatin, pravastatin, lovastatin, and 10 & 20 mg doses of simvastatin and the last sentence in the Medical Letter using the word “worrisome” is both ridiculous and 100% false – The pharmacokinetics of pitavastatin are extremely clean, better than all of the more lipophilic statins now on the market except fluvastatin (read the reference cited above which compares pitavastatin to all other statins using published data not invective). I cannot remember the last branded drug that was not first in its class to be released that the Medical Letter found any use for including Crestor which is why personally I find little use whatsoever for recommendations of the medical letter.

The Medical Letter does provide a nice summary of statins effectiveness and cost. As you can see Livalo (and any brand name statin) costs a lot more than generic rosuvastatin (276$ versus 8$) and is less effective

statins.png

 

Thus, there is no reason to use any brand name statin unless you have developed side effects on two generic statins with the second one being low dose rosuvastatin.

Anecdotal Pitavastatin Success

Four years ago I identified by vascular screening in one of my patients, a 65 year old woman a >50% blockage in the left  carotid artery.

We started her on 40 mg atorvastatin and she developed a rash. She was switched to rosuvastatin 10 mg and began waking up in the middle of the night with a headache and feeling light-headed. I thought it unlikely this symptom was due to the statin.

She requested that we go back to atorvastatin because she felt it likely the rash was from something else.one month later, complains of arms and legs are very sore and hard time getting dressed in the morning due to soreness. also constipated

We stopped the atorvastatin and a month later she called back indicating that she could feel her arteries clogging.

At this time we started Livalo at 2 mg twice weekly. LDL dropped by 50% to 71 mg/dl and she has tolerated it without side effects ever since.

Supporting Data

Beyond anecdotal support for pitavastatin in the statin intolerant patient we have one abstract presented at the ACC meetings in 2013.

A total of 40 consecutive patients with documented intolerance to any dose of at least two different statins were prospectively enrolled into a protocol whereby they received a trial of pitavastatin therapy at a dose of 2 mg per day.

Forty patients were enrolled and 27 of them (68%) were able to tolerate pitavastatin. LDL cholesterol was reduced from 147±27 mg/dL to 93±25 mg/dL, resulting in an average LDL-cholesterol reduction of 34%. Patients who could best tolerate pitavastatin tended to be males and those with no history of coronary artery disease or diabetes.



Despite what the Medical Letter says about pitavastatin I tend to agree with Tom Dayspring and I and most progressive preventive cardiologists will give pitavastatin at least a trial in our high risk patients with PSAS before giving up on statins in them.


Hydrophilicly  Yours,

-ACP

N.B. Pitavastatin was discovered in Japan by Nissan Chemical Industries and developed further by Kowa Pharmaceuticals, Tokyo. It has been extensively studied in Japanese studies.

The Livalo website tries to hint that their drug might be better/safer for those of Japanese ethnicity but the science on this is not clear. A review on the topic concludes

Pharmacokinetic investigations have noted higher plasma levels of statins in Asians compared with Caucasians, although postmarketing data for all statins have not identified any particular safety issues, even when statins are given at equivalent doses. The potential mechanisms of heightened response to statins in Asians are related to genetically based differences in the metabolism of statins at the level of hepatic enzymes and drug transporters. Studies indicate that lower statin doses achieve lipid improvements in Asian patients comparable with those observed with higher doses in Caucasians. In conclusion, prescribing lower starting doses of statins in Asians appears warranted while research on this subject continues.

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

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

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

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

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

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

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

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

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

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

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

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

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

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

perspective-1

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

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

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

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

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

“Frustrated” wrote

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

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

Mitch writes:

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

BIS wrote:

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

What Can We Do?

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

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

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

428 Senate Dirksen Office Building

Washington, DC 20510

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

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

Skeptically Yours,

-ACP

What Can You Really Learn From Celebrity Bob Harper’s Heart Attack And Near Sudden Death?

Until recently I had never heard of Bob Harper (The Biggest Loser) but apparently he is a celebrity personal trainer and had a heart attack and nearly died.  He  is known “for his contagious energy, ruthless training tactics, and ability to transform contestants’ bodies on The Biggest Loser” (a show I’ve never seen.)

When celebrities die suddenly (see Garry Sanders, Carrie Fischer) or have a heart attack at a youngish age despite an apparent healthy lifestyle this get’s people’s attention.

The media typically pounce on the story which combines the seductive allure of both health and celebrity reporting.

It turns out Harper inherited a high Lipoprotein (a) (see here) which put him at high risk for coronary atherosclerosis (CAD) which ultimately caused the heart attack (MI)  that caused his cardiac arrest.

To his credit, Harper has talked about Lipoprotein (a) and made the public and physicians more aware of this risk factor which does not show up in standard cholesterol testing.

Since his heart attack, Mr. Harper of “The Biggest Loser” has embarked on a newfound mission to raise awareness about heart disease and to urge people to get tested for lp(a).

Harper As Brilinta Shill

Unfortunately , he has also become a shill for Brilinta, an expensive brand name anti platelet drug often prescribed in patients after heart attacks or stents.

At the end of the TV commercial he says “If you’ve had a heart attack ask your doctor if Brilinta is right for you. My heart is worth Brilinta.”

At least this video is clearly an advertisement but patients and physicians are inundated  by infomercials for expensive, profit-driving drugs like Brilinta.

This Healthline article pretends to be a legitimate piece of journalism but is a stealth ad for Brilinta combined with lots of real ads for Brilinta.

Harper As Lifestyle Coach.

Harper also changed his fitness and diet regimens after his MI reasoning that something must have been wrong with his lifestyle and it needed modification.  For the most part he talks about more “balance” in his life which is good advice for everyone. His fitness regimens pre-MI were incredibly intense and have been toned down subsequently.

After his heart attack, Bob abandoned the Paleo lifestyle for the Mediterranean diet, as it’s been proven to improve heart health and reduce the risk of a heart attack, stroke, and heart-disease-related death by about 30 percent. But recently, he’s moved closer to a vegetarian regimen.

Of course, vegans and vegetarians have seized on this change in his diet as somehow proving the superiority of their chosen diets as in this vegan propaganda video:

Unfortunately there is no evidence that changing to a vegan or vegetarian diet will lower his risk of repeat MI.  Those who promote the Esselstyn, Pritikin or Ornish type diets claim to “reverse heart disease” and to be science-based but, as I’ve pointed  out (see here) the science behind these studies is really bad.

In fact, we know that neither diet nor exercise influence lipoprotein(a) levels which Bob inherited.  Some individuals just inherit the risk and must learn to deal with the cardiovascular cards they’ve been dealt.

What Can We Really Learn From Bob Harper’s Experience?

  1. Lipoprotein (a) is a significant risk marker for early CAD/MI/sudden cardiac death. Consider having it measured if you have a a) strong family history of premature deaths/heart attack (b) if you have developed premature subclinical atherosclerosis (see here) or clinical atherosclerosis (heart attack, stroke, peripheral vascular disease) or (c) a family member has been diagnosed with it.
  2. Everyone should learn how to do CPR and how to utilize an AED. (see here for my rant on these two incredibly important 3-letter words). Harper was working out in the gym when he collapsed. Fortunately a nearby medical student had the wherewithal to do CPR on him until he could be defibrillated back to a normal rhythm and transported to a hospital to stop his MI.
  3. Dropping dead suddenly is often the first indicator that you have advanced CAD. If you have a strong family history of sudden death or early CAD consider getting a coronary artery calcium scan to better assess your risk.

Focus on celebrities with heart disease helps bring awareness to the public about important issues but we can only learn so much about best lifestyle or medications from the experience of one individual, no matter how famous.

Brilliantly Yours,

-ACP

What John Mandrola Learned About Aspirin in Munich

The skeptical cardiologist did not get to travel to Munich to attend the recent European Society of Cardiology meetings but the electrophysiologist, John Mandrola did. He summarized two big trials which showed no benefit of aspirin in the primary prevention of cardiac disease, one in patients with diabetes and one in patients with moderate risk in Ten Things I Learned About Aspirin at ESC

Of note, the lack of benefit in these studies is partially related to a much lower rate of events than predicted from standard risk models.

Why? Mandrola notes:

“societal efforts, such as lower rates of smoking and removal of trans-fats from the food supply, have led to a heart-healthier environment. In addition, greater use of preventive therapies—statins and antihypertensive meds, for instance—have also contributed to lower rates of cardiac disease. These developments increase the difficulty of running trials for primary prevention but are decidedly good news for patients.”

Similar to the ASPREE study, aspirin did not show any benefit in reducing GI cancer in these two large studies.

So aspirin may be less effective than it was decades ago because we have done a good job overall of reducing the risk of heart attack and stroke.

acetylsalicylic ally Yours,

-ACP

h/t Reader Francis

Revisiting Who Should Take Aspirin

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

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

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

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

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

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

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

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

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

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

Screen Shot 2018-09-19 at 9.26.41 AM

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

 

Did Aspirin Reduce Cardiovascular Events?

No. It did not.

A separate paper analyzed cardiovascular outcomes

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

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

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

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

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

Who Should Take Aspirin?

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

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

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

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

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

Subclinical Atherosclerosis and Aspirin usage

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

 

Guided Use of Aspirin

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

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

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

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

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

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

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

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

Acetylsalicylically Yours,

-ACP

 

The inclusion criteria for ASPREE define significant cardiovascular disease as follows

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

Where Are My Generics Medications Made? India, China, or the US?

With the recent recall of valsartan due to carcinogenic Chinese contaminants the issue of where one’s generic medication is manufactured has become more important.

I take two generics: ramipril for my hypertension and rosuvastatin for my cholesterol/atherosclerosis and I had no idea where they came from when I discussed the rise of generics manufactured in China recently.

Where Is My Ramipril Made?

I called my St. Lukes pharmacist, Robert, and asked him if he could give me information on the origin of these pills.

Robert told me that my 10 mg ramipril capsule was distributed by a company called West-Ward located in New Jersey.  West-Ward was an independent Columbus, Ohio company but was purchased in 2016 by a very large pharmaceutical company , Hikma, based in Aaman, Jordan. Now the Hikma web site indicates West-Ward is no more and is simply called Hikma in the US.

According to a 2017  Columbus article

Hikma Pharmaceuticals Plc projects it will end 2017 with about $2 billion revenue, about $600 million of which is from generic drugs made by its U.S. subsidiary West-Ward. In the spring, the company had projected $800 million in generics sales.

Customer service at Hikma informs me that my ramipril was made in their Columbus, Ohio plant.

Where Is My  Rosuvastatin Made?

My rosuvastatin (generic of Crestor) was made by Glenmark Pharmaceuticals which, per wikipedia

 is a pharmaceutical company headquartered in Mumbai, India that was founded in 1977 by Gracias Saldanha as a generic drug and active pharmaceutical ingredient manufacturer; he named the company after his two sons.

Glenmark received FDA approval to market their generic rosuvastatin in the US in July, 2016. and at that time had 115 products authorized for distribution in the US market and 61 drugs pending approval with the US FDA.

My rosuvastatin according to Robert was made in India although the Glenmark product catalog does not reveal this information.

Generic versus Brand Name

I’ve talked about Crestor/rosuvastatin a few times on this blog and the development of a generic version has been very helpful for many of my patients. Looking online today I see that generic rosuvastatin goes for about 10$ per month compared to 260$ for Crestor.

Is it worth paying an extra 250$ per month to get brand name Crestor if, let’s say it was manufactured in the US? For most people it isn’t. For one thing, there is no guarantee of where your brand name drug is manufactured.

Crestor used to be made in a factory in Bristol, UK but this was shut down in 2017 and now I can’t tell where Astra-Zeneca makes the stuff. Frankly, I’m surprised that they are selling any of the drug which used to account for 5 billion dollars of their annual sales.

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

I never realized how globalized the pharmaceutical industry has become. Hopefully, the FDA is doing a good job of monitoring the safety and quality of products we rely on for our wellbeing which are manufactured all over the globe.

Skeptically Yours,

-ACP

Addendum: I have an updated post which includes more generic ARB recalls here

Is Your Generic Medication Made In China and Is It Safe?

Last week the FDA recalled several versions of the generic blood pressure medication valsartan which were made in China and contained a carcinogen (see here.)

Since then I  have switched many patients from the bad valsartan to losartan or valsartan from presumably safe manufacturers.

It didn’t really occur to me that this could be just the tip of the iceberg until I received a reader comment which I will copy below.

As I thought about it, I realized that I have no idea where the generic ramipril I am taking is manufactured. It very well could be in China or India.

This recent article from The Epoch Times confirms that Americans are becoming more and more reliant on medications manufactured in China and that many researchers feel this poses a significant security threat.

The Food and Drug Administration (FDA) is inspecting only a small number of the Chinese companies that manufacture U.S. drugs, and those it does inspect are often found to have serious health violations. Meanwhile, the drugs that are making their way into the United States from China, either as finished products or as ingredients, are often falling far below U.S. safety standards. And some of these drugs are not being inspected at all.

The book, “China RX: Exposing the Risks of America’s Dependence on China for Medicine” by Rosemary Gibson and Janardan Prasad Singh,” details the problem.

It is very hard to find out how many US drugs come from China since drug companies don’t make their sources apparent. In addition, even if the drugs themselves aren’t manufactured in China, Gibson and Singh write

“China is the largest global supplier of the active ingredients and chemical building blocks needed to make many prescription drugs, over the counter products and vitamins.”

Below are the comments of my reader:


This is horrible. We have a problem in the U.S. It is the infiltration of Chinese generics. I had no idea that this generic was being supplied by a Chinese maker. In fact, the bottles I got said “SOLCO” which is based in New Jersey. Now I’m painfully aware that SOLCO Healthcare US which is based in New Jersey, is owned by Zhejiang Huahai Paarmaceutical based in China’s Zhejiang Province. So this is the Chinese company’s subsidiary distributing this drug in the U.S. China has a long history of selling tainted products in the U.S. Chinese drywall, lead-based paint on toys, tainted pet food, etc. Now it is important to understand that 85% of prescriptions filled in the U.S. are generic. And insurance companies will not pay for brand when generic is available. My valsartan was about $30 for 90 days. Diovan is $750. I get it. But when these companies cut corners and people are endangered, something is wrong. I will never ever take another generic drug without first finding out where the product comes from. I know this is not perfect, but it is something. I think the U.S. lawmakers need to do something to make this information more transparent. It baffles me as to how this drug could have been tainted with a highly toxic chemical for so many years (they now say 4 years). This chemical is known to cause liver damage and cancer. Apparently the manufacturer changed the way it made the active ingredient which created this poison by-product. And now who do we hold accountable? How do we get to the bottom of what went wrong, and how to prevent this going forward. We have no way to compel anything in China. All that said, thanks for your information here it is helpful. I worry that the losartan is made by the same company – I will surely investigate.


China is also flooding the American market with useless OTC medications. I realized this when I looked closely at this “motion sickness patch” which is highly rated on Amazon.

It has no active ingredient which could be realistically thought to treat motion sickness yet is featured on Amazon’s motion sickness treatment section and is favorably reviewed by over a thousand users.

 

Unfortunately, in the US now users of medications must be very aware of the source and quality of the products they put in their body. Generic prescription medications and OTC products are highly likely to be manufactured out of the US and with minimal oversight.

Skeptically Yours,

-ACP

Addendum: I have a more recent post which includes additional recalls here.