Category Archives: Medication Side Effects

What Pain Medications Are Safe For My Heart?

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

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

What Is The Risk Of Pain Medications?

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increased risk of heart attack and heart failure with non steroidal anti-inflammatory drugs (NSAIDs) since Vioxx was withdrawn from the market in 2004.

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

The findings:

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

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

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

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

My Current Patient Advice on Cardiac Safety of Pain Meds

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

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

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

Therefore, if at all possible avoid NSAIDS.

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

Treating The Whole Patient

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

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

A recent review concluded

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

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

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

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

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

Analgesically Yours,

-ACP

What Cold Medications Are Safe For My Heart: 2016 Update

The most popular  skeptical cardiologist post is one written a year ago concerning over-the-counter (OTC)  cold medications.

Little has changed in the 8 billion dollar world of useless and confusing OTC  cold, flu, and sinus medications since then.

I still advise avoiding them and utilizing specific medications for specific symptoms.

I’m updating the article with additional comments on two frequently encountered drugs that I did not cover originally.

Alka-Seltzer Plops Into The OTC Cold Market 

I had always viewed Alka-Seltzer as an effervescent tablet which was a treatment for acid reflux, a.k.a. upset stomach, but the brand (now owned by Bayer) has moved aggressively into the bewildering morass of over the counter OTC cold meds. Indeed, when Alka-Seltzer began in 1931 it was a combination of aspirin and sodium bicarbonate (baking soda) marketed for upset stomachs. Popular commercials from the 1960s featured the catchy jingle (still stuck in my head) “Plop, Plop, Fizz, Fizz. Oh What a Relief It Is” often sung by Speedy, an odd anthropomorphic creature with an Alka-Seltzer thorax and cap.

(The jingle was written by Tom Dawes of The Cyrcle (Red Rubber Ball) and not by the father of Juliana Margulies)

Recently, I  received a request from an out-of-town guest who was suffering from a cough and upper respiratory infection (URI) to purchase Alka-Seltzer plus in the form of a tablet that dissolves in hot water .

At his request, Alka-Seltzer Plus Day Multi-Symptom Cold and Flu was purchased at the local Walgreen’s.

The ingredients are typical for many of  the Alka-Seltzer products:

-dextromethorphan (promoted for cough but ineffective with considerable side effects, see my initial post)

-acetaminophen (Tylenol, for pain and fever)

-phenylephrine (decongestant )

Phenylephrine: Ineffective Substitute for Pseudoephedrine

I didn’t cover phenylephrine in my previous post. It has taken the place of pseudoephedrine in  on the shelf over the counter URI (OTSOTCURI) medications.

Like pseudoephedrine, phenylephrine is a sympathomimetic drug, meaning it stimulates receptors of the sympathetic nervous system. Unlike pseudoephedrine, phenylephrine is useless as a decongestant when taken in the dosages available over the counter.

A study published in february, 2015 confirmed what previous studies had suggested: phenylephrine in dosages of 10 to 40 mg daily was no more effective than placebo in reducing symptoms of nasal congestion.

An accompanying editorial called on OTSOTCURI manufactures to remove this useless drug from their products.

Alas,  all of the Alka-Seltzer preparations that claim to treat congestion utilize phenylephrine as the decongestant.

The transition to useless phenylephrine took place when pseudoephedrine was taken off the shelves and put behind the counter to reduce its usage in making methamphetamine.

Therefor, Alka-Seltzer plus multi-symptom cold and flu contains two useless ingredients plus acetaminophen (Tylenol).

You can buy a large bottle of cheap generic acetaminophen and take exactly the right dose you need for relieving fever or body aches without paying for two useless accompanying drugs which have the potential for giving you unwanted side effects.

Nighttime Sleep Aids In OTC Cold Meds

I covered the most common drug found in OTC cold meds that are promoted for nighttime use, diphenhydramine/benadryl, in my previous post.

Nighttime Alka-Seltzer products contain a similar sedating antihistamine called doxylamine succinate. For example , Alka-Seltzer Severe Cold and Cough Liquid Night (ASCCLN) contains:

-Acetaminophen 650 mg

-Dextromethorphan hydrobromide 30 mg

-Doxylamine succinate 12.5 mg

Doxylamine is the active ingredient in the brand name sleep aid Unisom and the “ZZquil” products from the Nyquil brand that are promoted for inducing sleep. It is available in cheap, generic form at a cost of 7.90$ for 96 25 mg tablets.  According to drugbank.ca:

“It is also the most powerful over-the-counter sedative available in the United States, and more sedating than many prescription hypnotics. In a study, it was found to be superior to even the barbiturate, phenobarbital for use as a sedative.”

Note that the effective dosage recommended in separate sleep aids is 25 mg not the 12.5 mg found in Alka-Seltzer OTC cold meds, Thus, if you want an effective dosage of doxyylamine to help you sleep, you must double the recommended dosage of Alka-seltzer  SCCLN  which gives you too much acetaminophen and dextromethorphan.

Doubling these drugs raises the potential for side effects. Common dextromethorphan side effects include nausea/vomiting, dizziness, diarrhea, nervousness. Too much acetaminophen can damage the liver.

In addition, both dextromethorphan and acetaminophen interact with multiple other medications. Dextromethorphan is known to interact with 76 medications.

Acetaminophen can increase the INR (measure of blood thinning) in patients taking warfarin and increase the risk of dangerous bleeding.

As I summarized previously:

“I think you are much better off avoiding these brand name mixtures of different active ingredients.

Instead, you should take what you need for a specific symptom in the appropriate dosage and time interval.

Thus, if you have pain, take  the minimal dose of tylenol that relieves it and repeat when it comes back.

If you have a cough, recognize that the OTC ingredients are no better than placebo and are being abused as recreational drugs. Most coughs go away shortly but if one is particularly troublesome and persistent get a cough suppressing drug from your physician.

If you have a really runny nose with a lot of sneezing it is probably OK to take pseudoephedrine even if you are a heart patient or have high blood pressure. Take it as I described above. Start with 30 mg of the little red pseudoephedrine pills , wait an hour to see how you feel. Take a second if it has not been effective.  Repeat at 4-6 hour intervals as needed. Take your blood pressure at least once after starting it.

Don’t buy the multi-symptom multiple ingredient combinations which are simply a marketing tool to get you to spend more money on something from which you won’t benefit.”

Hypnotically Yours,

-ACP

 

Foxglove Equipoise

I came across the word equipoise, used eight times, in a recent, brief editorial entitled “Digoxin: In the Cross Hairs Again.”

It’s not a word I hear outside of medical circles but it serves a great function in the clinical arena.

When used in medicine as in the phrase “clinical equipoise” it means that medical experts are uncertain as to whether a treatment for a disease is helpful.

Thus, for digoxin, a drug which has been utilized for patients with heart failure or atrial fibrillation for 240 years, we still don’t know if the benefits outweigh the risks.

foxgloveDigoxin is the major medicinally active chemical in the foxglove plant which was first described by Leonhart Fuchs (the plant and color fuchsia are named after him), a German botanist and physician in 1542. It was given the latin name digitalis purpurea, reflecting the plant’s purplish color and similarity to a thimble (German finger hut).

A vague understanding that the foxglove had medicinal and toxic properties existed in subsequent centuries, but it took a very observant physician from the West of England, William Withering, to give it a sold footing in the medical pharmacopeia.

Withering collected 10 years of his observations, using various preparations of foxglove to treat various diseases including the mysterious “dropsy” in the (now famous) An Account of the Foxglove and some of its Medical Uses.”

He writes of his rationale for beginning to give patients foxglove:

“In the year 1775, my opinion was asked concerning a family receipt for the cure of the dropsy. I was told that it had long been kept a secret by an old woman in Shropshire who had sometimes made cures after the more regular practitioners had failed. I was informed also, that the effects produced were violent vomiting and purging; for the diuretic effects seemed to have been overlooked. This medicine was composed of twenty or more different herbs; but it was not very difficult for one conversant in these subjects, to perceive, that the active herb could be no other than the Foxglove.”

(Excerpt From: William Withering. “An Account of the Foxglove and some of its Medical Uses.” iBooks. https://itun.es/us/ZeJDE.l)

Dropsy was that era’s term for edema: “The dropsy is a preternatural swelling of the whole body, or some part of it, occasioned by a collection of watery humour. It is distinguished by different names, according to the part affected, as the anasarca, or a collection of water under the skin; the ascites, or a collection of water in the belly; the hydrops pectoris, or dropsy of the breast; the hydrocephalus, or dropsy of the brain, &c. [Buchan1785].”

Foxglove was in clinical equipoise in 1775. When Withering started giving it to his patients with dropsy he did not know if it would help or harm them.

After trying various preparations of the foxglove in varying dosages in hundreds of patients he concluded that it was of a great benefit as long as it was carefully titrated to avoid the toxicities of overly slow pulse and vomiting.

With modern medicines that are proven to be safe and effective we demand evidence from randomized controlled trials in which the active drug is compared to a placebo. There are too many factors which affect the course of a disease to accept the kind of observational evidence that Withering collected.

Digitalis is currently utilized in heart failure and atrial fibrillation. Withering’s patients likely had one or both of these conditions.

A recent observational study found that digitalis usage in patients with newly diagnosed atrial fibrillation was associated with a 26% higher risk of dying.

The only large randomized trial of digoxin, the DIG (Digitalis Investigation Group) trial, showed no effect on mortality, but digoxin did reduce hospitalization among patients with heart failure and a reduced ejection fraction (HFrEF)

The DIG study was performed in the early 1990s, before current optimal treatment regiments for heart failure with reduced ejection fraction were developed and may no longer relevant. More recent observational studies suggest digoxin raises mortality in heart failure.

Thus, the foxglove or digitalis, although used for 240 years in hundreds of thousands of patients for both heart failure and atrial fibrillation remains in clinical equipoise.

Doctors must be very circumspect in prescribing this medicine. Personally, I do not use digoxin in heart failure patients.

I use digoxin in chronic atrial fibrillation only as a last resort when other agents do not allow adequate slowing of the heart rate and I carefully monitor levels and kidney function if a patient is on it.

jemimafoxglove
From The Tale of jemima Puddle-Duck. Jemima… rather fancied a tree-stump amongst some tall fox-gloves.

I have, however, decided to start growing foxglove in my garden. I will try to warn the ducks, rabbits and squirrels not to partake of its beautiful flowers as they might prove deadly.

I also plan to visit the grave of Withering on my upcoming trip to Europe, for upon his tombstone it is said, there is an engraving of the foxglove!

 

 

Digitally Yours,

-ACP

Low T and Me: Does Testosterone Therapy Increase Cardiovascular Risk?

In the last year, several of my patients have asked me whether it is safe for them to take testosterone for “low T.” They were responding to media reports suggesting that testosterone therapy raised heart attack risk by one-third.

I must admit, I had been skeptical of the legitimacy of the “low T” diagnosis.  Many of the symptoms attributed to testosterone (T) deficiency, it seemed, were just part of normal male aging: decreased libido, fatigue, weight gain, and loss of muscle mass.

Perhaps, I thought, men should just be more willing to exercise regularly and lose weight and accept the indignities of aging that result despite our best efforts.

On the other hand, in the back of mind was the idea that perhaps I, as a sixty-something male with declining strength and endurance, could somehow forestall the ravages of aging by taking T.

I googled “low T” and immediately found some sponsored sites, including “is it low T.com,” which appears to be an educational site for patients. However, the one treatment option that they provide links to is made by Abbvie, the somewhat hidden host of the site. Abbvie is a pharmaceutical company that makes Androgel, the most widely prescribed testosterone cream.

lowTquiz

I answered yes to the 3 questions I thought were just uniform consequences of aging:

1. Reduction in strength and/or endurance.

2. Loss of height.

3. Deterioration in your ability to play sports.

After taking the quiz, I was told that answering yes to 3 of the 10 questions strongly suggests you have low T.

In addition, according to the site, if you answered yes to question 1 (decreased libido) or 7 (less strong erections) you have low T.

Based on this quiz, I and 99% of men my age must have low T!!

In the last 10 years, the use of testosterone therapy has quadrupled, driven by better formulations for testosterone delivery and by direct-to-consumer marketing campaigns that suggest that treating low T will reverse these normal consequences of aging.

As a result, in 2013, 2.3 million American men received testosterone therapy and 25% of these men had no baseline testosterone levels tested.

A year ago, the New York Times editorial board opined on the dangers of overprescribing testosterone and the influence of pharmaceutical companies in over-promoting the drug, in a piece entitled “Overprescribing testosterone, dangerously.”  Articles like this are what have raised patients’ concerns about T therapy and increased risk of heart attack.

Testosterone and Mortality

There is a large body of evidence that shows an association between lower T levels and increased mortality and coronary artery disease. Lower T levels are also associated with higher risk of diabetes and the metabolic syndrome.  Studies also show that T therapy in T-deficient men increase lean mass and reduce fat mass and are associated with a reduction in mortality. A recent review article by Morgenthaler, et al in Mayo Clinic Proceedings, provides a detailed and meticulous summary of these studies and data.

Two recent studies contradict this large body of evidence and gained enormous media attention. The first, by Vigen et al in JAMA 2013, was a retrospective analysis of VA patients which has received extensive criticism for its statistical technique and has been corrected twice. The second study was by Finical, et al in PLoS One 2014, suggesting increased mortality in patients for 90 days after receiving their prescription for T. This study also contains methodologic issues and is hardly conclusive.

Is it Safe to Take T for low T

My recommendation to patients who want to take T after looking at all the data is as follows:

-Make sure that you really have low T.  Your total T levels should be less than 300 ng/dL done in a reliable, certified lab.

-At this time, I don’t see solid evidence that taking T, if you definitely have T deficiency, increases the risk of cardiovascular complications or death.

As with all medications, the shortest duration and smallest effective amount is what you should take. All medications have side effects, some that we know and some that we don’t know. Most of the studies that have been published were on small numbers of patients for short periods of time.

-If you are overweight and/or sedentary, there is good evidence that losing weight and exercising will improve many of the symptoms ascribed to low T.  These will also improve your life expectancy and lower your risk of heart attack.

…And you won’t have to worry about any side effects!

Do I have low T? Like all sixty-somethings my T levels are lower than when I was 30. My endurance is less. I’m losing height. Fat wants to build up in my abdomen, despite my best efforts.

It’s only going to get worse, but I’m willing to accept these as normal consequences of the aging process, rather than introduce external T into my system with its unknown consequences.

I will not go gentle into that good night but will continue to rage against the dying of the light without the wonders of pharmaceutical grade T.

Yours in aging,

-ACP

 

 

 

 

 

Moogfest, the Z-pak, the QT interval and Sudden Cardiac Death


kraftwerk
The skeptical cardiologist was planning on attending Moogfest 2014 in Asheville, North Carolina last weekend. I was going with the old friend and life coach of the skeptical cardiologist (OFLCSC) and planned on taking in electronic and synthesizer legends like Kraftwerk and Keith Emerson, riding bikes and drinking lots of craft beer. Unfortunately, a very bad upper respiratory infection took hold of me, progressing to what felt like a pneumonia (shaking chills, fever, coughing up dark, thick sputum, rattling emerging from the depths of my lungs) and I had to cancel the trip.

After processing multiple factors of risk versus benefit (not to mention the contribution to resistant bacteria), I decided to start myself on a Z-pak which is commonly utilized for community acquired pneumonia (does this mean I have a fool for a doctor?)

Azithromycin (the macrolide antibiotic in the Z-pak) , due to its broad antibiotic spectrum and perceived favorable safety profile, became one of the top 15 most prescribed drugs and the best-selling antibiotic in the United States, accounting for 55.4 million prescriptions in 2012.

The time between onset of electrical activation of the ventricles (Q) and the depolarization or reset of the ventricles (T) is called the QT interval. You can be born with a prolonged QT interval or it can become prolonged due to certain conditions. Prolonged QT intervals increase risk of sudden death
The time between onset of electrical activation of the ventricles (Q) and the depolarization or reset of the ventricles (T) is called the QT interval. You can be born with a prolonged QT interval or it can become prolonged due to certain conditions. Prolonged QT intervals increase risk of sudden death from abnormal rhythms like torsades de pointes type of ventricular tachycardia

Between 2004 to 2011, the FDA received 203 reports of azithromycin-associated QT prolongation (see graphic to the left) Torsades de Pointes (graphic) ventricular arrhythmia, or, in 65 cases, sudden cardiac death.

This prompted a review of Tennessee medicaid data which was published in 2012.

tdp
Torsades Des Pointes (fancy French word  for twisting of the points: note how the deflections seem to be oscillating slowly (somewhat like a sine wave I would have heard at Moogfest) . This is felt to be the way QT prolongation from medications like the Z-pak cause sudden death.

This study found that people taking azithromycin over the typical 5 days of therapy, had a rate of cardiovascular death 2.88 times higher than in people taking no antibiotic, and 2.49 times higher than in people taking amoxicillin. Most of the risk appeared to be those patients who had a baseline high risk of cardiovascular disease and the excess risk of death resolved after the 5 days of therapy.

As a result, the FDA added a warning to the azithromycin package insert and urged health care professionals to use caution  when prescribing it to patients known to have risk factors for drug-related arrhythmias, including those with long QT intervals, either congenitally or induced by drugs, low potassium or magnesium levels, slow heart rates or on other medications drugs used to control abnormal heart rhythms (amiodarone, sotalol and dofetilde). 

I survived my 5 day brush with a three-fold increased risk of sudden death and I really think the Z-pak substantially helped me get over the bacterial lung infection I felt I had. I knew my risk factors in detail and they were low. I was totally aware of any interacting drugs that could prolong my QT interval.

You can survive too. Make sure you definitely need the drug (i.e. you have a bacterial infection not just the common cold) and be cautious if you have any of the following

  • Family history of sudden death
  • Personal history of unexplained passing out or dizziness
  • Use of other medications that prolong QT interval (PDF)
  • Low potassium or magnesium levels (not uncommon in heart failure patients who are on water pills)
  • Severe heart disease of any kind

A complete listing is available here.

Meanwhile, Enjoy a sample of whatl I missed at Moogfest: Dorit Chrysler playing the theremin