All posts by Dr. AnthonyP

Cardiologist, blogger, musician

Italy And The Valsalva Manouevre

Antonio Maria Valsalva (1666-1723) was an Italian anatomist, physician and surgeon whose name is familiar to cardiologists for two reasons. First, he described what are now termed the sinuses of Valsalva, the three areas of dilatation in the proximal portion of the aorta just outside the opening of the aortic valve.

Second, in his textbook on the ear, De aure humana tractatus, published in 1704 in Bologna, he showed an original method of inflating the middle ear (now called Valsalva’s manoeuvre) in order to expel pus. A variation of this classic Valsalva maneuver is used frequently in cardiology for diagnostic and therapeutic purposes.

The skeptical cardiologist and his newly-minted bride, will be jetting off to Italy in a few weeks but, alas, we are not visiting Bologna. Hopefully we won’t need to utilize the original Valsalva manouevre to equalize the pressure between our middle ears and the cabin atmosphere in order to prevent otic barotrauma as we descend.

I don’t feel so bad about the rock because the wikipedia caption reads as follows:Sections of Hadrian’s Wall remain along the route, though much has been dismantled over the years to use the stones for various nearby construction projects.

I’ve been fascinated by the Roman Empire since I took Latin in high school. I was so obsessed with all things Roman that when my family traveled back to England to visit relatives and such, I insisted on us visiting Hadrian’s Wall. Don’t tell the authorities, but I still possess a rock I took from said wall.

The only time I’ve been to Italy was 30 years ago after presenting at the European Society of Cardiology meeting in Nice, France. I foolishly rented a car and drove north to Lago Maggiore. It was one of the most harrowing experiences of my life.

The Italian Itinerary

This time we are flying into Rome and then taking a train to Florence.

From Florence I’m planning to rent a car (having failed to learn my lesson) to drive to La Foce, an historic estate, which lies on the hills overlooking the Val d’Orcia.

La Foce

We’ll spend two nights in the B&B portion of this place, which sounds amazing:

Midway between Florence and Rome, it is also within easy reach of Siena, Arezzo, Perugia, Assisi, Orvieto. Renaissance and medieval gems such as Pienza, Montepulciano, Monticchiello and Montalcino are only a few miles away. The countryside abounds in lovely walks among woods and the characteristic crete senesi (clay hills); the food is among the best in Tuscany and famous wines such as the Vino Nobile and Brunello can be tasted in the local cellars. The Val d’Orcia has recently been included among the World Heritage sites of UNESCO.

From the heart of Tuscany, we then drive to the coast of northern Tuscany to meet up with the in-laws in Viareggio.

Manarola

 

After a few nights in Viareggio with Geo (the man on the statin fence) and Wendy, we will all take a ferry to the Cinque Terra, staying in Manarola.

Lastly, we will travel to Milan, and then fly home.

I’ve got a good idea of what the top tourist destinations are in these cities from reading Rick Steves’ book on Italy and from discussions with friends who have been there.

However, we typically prefer wandering semi-aimlessly in great cities, rather than dealing with large tourist herds at the must-see attractions.

I’m actually more interested in La Specola in Florence than I am in seeing Michaelangelo’s David. La Specola:

spans 34 rooms and contains not only zoological subjects, such as a stuffed hippopotamus(a 17th-century Medici pet, which once lived in the Boboli Gardens), but also a collection of anatomical waxes (including those by Gaetano Giulio Zumbo and Clemente Susini), an art developed in Florence in the 17th century for the purpose of teaching medicine. This collection is very famous worldwide for the incredible accuracy and realism of the details, copied from real corpses. Also in La Specola on display are scientific and medical instruments. Parts of the museum are decorated with frescoes and pietra dura representing some of the principal Italian scientific achievements from the Renaissance to the late 18th century.

I tend to rely on Rick Steves’ books for European travel, but if any readers have experience in these Italian areas please feel free to add them to the comments section or send me an email at dr._pearson@icloud.com. I would be especially interested in “off-the-beaten path” things of interest (especially if they have a literary, medical or scientific connection) and restaurant recommendations.

 

To all my patients, please accept my apologies for any rescheduling this may have caused.

In my absence you will be in good hands as my partners, primarily Brian Kaebnick, will be covering for me.

Arrivederci!

-ACP

Are You Doing Enough Push Ups To Save Your Life?

The skeptical cardiologist has always had a fondness for push-ups. Therefore I read with interest a recent study published in JAMAOpen which looked at how many push-ups a group of 30 and 40-something male firefighters from Indiana could do and how that related to cardiovascular outcomes over the next ten years.

The article was published in the peer-reviewed journal JAMA Network Open, and is freely available to access online.

The British National Health Service pointed out that “The UK media has rather over exaggerated these findings:”

Both the Metro and the Daily Mirror highlighted the result of 40 push-ups being “the magic number” for preventing heart disease, but in fact being able to do 10 or more push-ups was also associated with lower heart disease risk.

What Was Studied?

The study involved 1,104 male firefighters (average age 39.6) from 10 fire departments in Indiana who underwent regular medical checks between 2000 and 2010. 

At baseline the participants underwent a physical fitness assessment which included push-up capacity (hereafter referred to as the push-up number (PUN))and treadmill exercise tolerance tests conducted per standardized protocols.

For push-ups, the firefighter was instructed to begin push-ups in time with a metronome set at 80 beats per minute. Clinic staff counted the number of push-ups completed until the participant reached 80, missed 3 or more beats of the metronome, or stopped owing to exhaustion or other symptoms (dizziness, lightheadedness, chest pain, or shortness of breath). Numbers of push-ups were arbitrarily divided into 5 categories in increments of 10 push-ups for each category. Exercise tolerance tests were performed on a treadmill using a modified Bruce protocol until participants reached at least 85% of their maximal predicted heart rates, requested early termination, or experienced a clinical indication for early termination according to the American College of Sports Medicine Guidelines (maximum oxygen consumption [V̇ O2max]).

The main outcomes assessed were new diagnoses of heart disease from enrollment up to 2010. 

Cardiovascular events were verified by periodic examinations at the same clinic or by clinically verified return-to-work forms. Cardiovascular disease–related events (CVD) were defined as incident diagnosis of coronary artery disease or other major CVD event (eg, heart failure, sudden cardiac death)

Here’s the graph of the probability of being free of a CVD event on the y-axis with time on x-axis.

The black line represents those 75 firefighters who couldn’t make it into double digits, the green those 155 who did more than 40 pushups.

Participants able to complete more than 40 push-ups had a significant 96% lower rate of CVD events compared with those completing fewer than 10 push-ups.

It is surprising that the push up number seemed a better predictor of outcomes than the exercise test, This should be taken with a grain of salt because although the investigators report out “VO2 max” the stress tests were not maximal tests.

The firefighters with lower push up numbers were fatter, more likely to smoke and had higher blood pressure, glucose and cholesterol levels.

What useful information can one take from this study?

You definitely cannot say that being able to do more than 40 pushups will somehow prevent heart disease. The PUN is neither causing nor preventing anything.

The PUN is a marker for the overall physical shape of these firefighters. It’s a marker for how these men were taking care of themselves. If you are a 39 year old fireman from Indiana and can’t do 11 push-ups you are in very sorry condition and it is likely evident in numerous other ways.

The <11 PUN crew were a bunch of fat, diabetic, insulin resistant, hyperlipidemic, out-of-shape hypertensives who were heart attacks in the waiting.

Push-ups Are A Great Exercise

Despite the meaningless of this study you should consider adding push-ups to your exercise routine. Doing them won’t save your life but it will contribute to mitigating the weakness and frailty of aging. Don’t obsess about your PUN.

I’ve always liked push-ups and highly recommend them. They require no special equipment or preparation. It’s a quick exercise that builds upper body muscle strength, adds to my core strength and gets my heart rate up a bit. For some reason my office in O’Fallon is always cold so several times during the day when I’m there I’ll do 100 jumping jacks and drop on the carpet and do some push-ups in an effort to get warm.

I don’t do them every day but the last time I tried I could do 50 in less than a minute and that has me convinced I will live forever!

Calisthenically Yours,

-ACP

N.B. In my post on mitigating sarcopenia in the elderly I talked about the importance of resistance exercise:

Americans spend billions on useless supplements and vitamins in their search for better health but exercise is a superior drug, being free  and without drug-related side effects

I’ve spent a lot of time on this blog emphasizing the importance of aerobic exercise for cardiovascular health but I also am a believer in strength and flexibility training for overall health and longevity.

As we age we suffer more and more from sarcopenia-a gradual decrease in muscle mass.

Scientific reviews note that loss of muscle mass and muscle strengh is quite common in individuals over age 65 and is associated with increased dependence, frailty and mortality

Push-ups are a great resistance exercise. For a description of the perfect form for a push up see here.

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

In Historic Moment, Transcatheter Aortic Valve Replacement Proven Superior to Surgical AVR

Three years ago after hearing two amazing presentations at the ACC meeting the skeptical cardiologist opined:

These studies suggest to me for the first time that TAVR may ultimately replace SAVR for all patients with severe aortic stenosis, low to high in their risk for surgery.

Clearly, we need ongoing follow up of these patients and more long term data, but as these devices improve and the operators gain more experience it is likely that results will only get better.

This represents a huge paradigm shift in our approach to valvular heart disease.

This morning I watched two more amazing study presentations at the ACC meeting in New Orleans which unequivocally establish the minimally invasive TAVR procedure (which my cardiology colleagues perform here at St. Luke’s) as the treatment of choice for patients who have symptoms related to severe narrowing of their aortic valve (aortic stenosis).

I just published a piece on the presentations for the physician social media site, SERMO which follows:

Since 2015 it’s been clear to me that catheter-based procedures (TAVR) were a better option than open-heart surgical aortic valve replacement for most of my patients with severe symptomatic aortic stenosis who were at high (>8% STS )  and intermediate (>4% STS) risk for surgery.  

Based on continued durability of TAVR results and outstanding results in my own institution, I’ve been advising my low risk patients with severe aortic stenosis that it was only a matter of time before TAVR would become the best option for them.

At the American College of Cardiology Meetings in New Orleans this morning two back to back presentations have confirmed that TAVR should be considered the treatment of choice rather than surgical aortic valve replacement ( SAVR) for most low risk patients with severe symptomatic AS.

This is such a dramatic paradigm shift in the treatment of AS that the Eugene Braunwald (now 90 years old) the first discussant of the presentations after reviewing the history of the treatment of AS, described it as an “historic moment” , one that we will tell our grandchildren that we were present at.

Furthermore, in a display I’ve never seen at an ACC session, the audience spontaneously stood and gave the presenters a standing ovation. 

Both studies were published yesterday in the NEJM (something the presenters indicated was an error) and disappointingly I read the results described in a New York Times article prior to watching the live presentation.

The first presentation was from Martin Leon on the Partner 3 trial which utilizes the Edwards Sapien 3, third generation baloon-expandable valve. The study randomized 1,000 patients to either TAVR  or standard SAVR with a bioprosthetic valve. The primary endpoint was the composite of death from any cause, stroke or re-hospitalization at one year after the procedure. At one year, the primary endpoint occurred in 8.5 percent of the TAVR group compared with 15.1 percent of the surgery group, meeting the requirements for both noninferiority (p<0.001) and superiority of TAVR vs. surgery (p<0.001).

The Kaplan-Meir analysis of the primary endpoint components with TAVR vs. surgery found mortality rates of 1.0 percent vs. 2.5 percent, stroke rates of 1.2 percent vs. 3.1 percent, and rehospitalization rates of 7.3 percent vs. 11.0 percent, respectively. The length of hospital stay was reduced from seven to three days with TAVR.

A cardiac surgeon, Michael Reardon (who I described as cocky and folksy in my 2015 post on TAVR), presented the results of the  EVOLUT  trial which randomized 1,468 patients to TAVR with a self-expanding bioprosthesis compared with surgical replacement. The primary endpoint was the composite of death from any cause or disabling stroke at 24 months. At 24 months, death or disabling stroke occurred in 5.3 percent of the TAVR group compared with 6.7 percent of the surgery group,

At 30 days, TAVR was statistically superior to surgery for the secondary combined endpoint of all-cause mortality or disabling stroke (0.8 vs. 2.6 percent). Patients receiving TAVR had significantly better quality of life and hemodynamics at 30 days.

I concur that these studies represent tremendous data that will drive a paradigm shift in the treatment of AS and anticipate that we will rapidly receive approval to use these two TAVR devices in all patients who meet the entry criteria (note that bicuspid AV was an exclusion but a subsequent presentation at ACC19 suggests that outcomes are similar in bicuspid valve patients to tricuspid valve patients).

Transfemorally Yours,

-ACP

Apple Heart Study: Despite The Ballyhoo, No Benefits Demonstrated, Harms Not Measured

The results of the Apple Heart Study, were presented this morning at the American College of Cardiology Scientific Sessions amid intense media scrutiny. The AHS is a “prospective, single arm pragmatic study” which had the primary objective of measuring the proportion of participants with an irregular pulse detected by the Apple Watch who turn out to have atrial fibrillation on subsequent ambulatory ECG patch monitoring.

 

I and over 400,000 other Apple Watch owners participated in the AH study by downloading the Apple Heart Study app and self-verifying our eligibility. 

My assessment is that we have learned little to nothing from the AHS that we didn’t already know. I’m also concerned that many patients suffered anxiety or unnecessary testing after being referred to urgent care centers, emergency departments, cardiologists or primary care providers and the results of these inappropriate referrals may never be determined.

Here is the study in a nutshell:

  1. Participants enrolled by submitting  information using the iPhone Heart Study app and none of their isubmitted nformation was verified.
  2. An irregular pulse notification was issued to 0.5% of participants who were then  contacted and asked to participate in a Telehealth visit with a doctor (who we will call Dr. Appleseed)
  3. Only 945 of the 2161 who received a pulse notification participated in the first study visit.
  4. Interestingly, Dr. Appleseed was empowered to send participants to the ER if they had symptoms (chest pain, shortness of breath, fainting/losing consciousness) It is not clear how many were sent to the ER and what their outcomes were but this flow diagram shows that 20 were excluded from further testing due to “emergent symptoms.”

  5. Another 174 participants were excluded after finding out at the first visit that they had a history of afib or aflutter and 90 due to current anticoagulant use (both of these factors were exclusion criteria which gives us an idea of how accurate the information was at the time of participant entry.)
  6. After all these exclusions only 658 ECG monitor patches were shipped to the participants of which only 450 were returned and analyzed.
  7. This means of the original 2161 participants who were notified of pulse irregularity, the study only reports data on 450 or 21%. Such a low rate of participation makes any conclusions from the study suspect.
  8. Of the 450 ECG patches analyzed only 34% were classified as having afib. Only 25% of this afib lasted longer than 24 hours.
  9. After the patch data was analyzed, patients had a second Telehealth visit with Dr. Appleseed who reviewed the findings with the patient. Per the initial published description of the methods of the AHS (see here) Dr. Appleseed  would tell the participant to head to the ER if certain abnormalities were found on the ECG.

Per the study description (apple heart study), Dr. Appleseed recommended a visit to the PCP for “AF or any other arrhythmia” detected by the patch:”

“If AF or any other arrhythmias have been detected in reviewing the ambulatory ECG monitor data, or if there are other non-urgent symptom identified by the study physician during the video visit that may need further clinical evaluation, the Study Telehealth Provider directs the participant to his or her primary health care provider”

At this point it seems likely that a lot of participants were instructed to go see their PCPs. Because as someone who looks at a lot of 2 week ambulatory ECG recordings I know that is the rare recording that does not show “other arrhythmias.”

Even more distressing is the call that participants would have received based on “the initial technical read:” I’m presuming this “technical read” was by a technician and not by a cardiologist. In my experience, many initial reads from long term monitors are inaccurate.

“If the initial technical read identifies abnormalities that require urgent attention (ventricular tachycardia or ventricular fibrillation, high-degree heart block, long pauses, or sustained and very rapid ventricular rates), then the participant is contacted immediately and directed to local emergency care or advised how to seek local emergency care.”

I wonder how many  ERs had AHS participants show up saying they had been told they had a life-threatening arrhythmia? How much down stream testing with possible invasive, life-threatening procedures such as cardiac catheterization were performed in response to these notifications?

Overall, these findings add nothing to previous studies using wearable PPG technology and they certainly don’t leave me with any confidence that the  Apple Watch is accurately automatically detecting atrial fibrillation.

Was more harm than good done by the Apple Heart Study?

We will never know. The strength of this study, the large number of easily recruited participants is also its Achilles heel. We don’t know that any information about the participants is correct and we don’t have any validated follow up of the outcomes. In particular, I’m concerned that we don’t know what happened to all of these individuals who were sent to various health care providers thinking there might be something seriously wrong. 

Perhaps Apple and Stanford need to review the first dictum of medicine: Primum Non Nocere, First Do No Harm.

Tachogramophobically Yours,

-ACP

Should All Patients With A High Coronary Calcium Score Undergo Stress Testing?

Coronary artery calcium (CAC) scans are an excellent tool for better defining coronary heart disease risk in many individuals. In light of the recent ACC/AHA guidelines endorsement of CAC, the skeptical cardiologist anticipates that primary care physicians will be ordering more and will often be faced with the question of what to do with abnormally high results.

There are two, diametrically opposed viewpoints which have been taken on this issue.

The Argument For Stress Testing

The majority of cardiologists are likely to fall into the camp of “more testing is good” which was summarized in a  State of The Art article that Dr. Harvey Hecht wrote in JACC recently.

The argument appears logical and is as follows:

  1. There is a high yield of abnormal results from stress testing when done on patients with high CAC.

The appropriateness of stress testing after CAC scanning in asymptomatic patients is directly related to the CAC score. The incidence of abnormal nuclear stress testing is 1.3%, 11.3%, and 35.2% for CAC scores 400, respectively .

2. The higher yield for ischemia/abnormal tests in patients with >400 CAC implies the ability to further risk stratify patients thus leading to guideline recommendations:

It is only in the >400 group that the pretest likelihood is sufficiently high to warrant further evaluation with myocardial perfusion imaging, for which there is a IIb recommendation

Hecht references a 2010 guideline issued by ACC/AHA (2010 ACCF/AHA Guideline for Assessment of Cardiovascular Risk in Asymptomatic Adults) which states

1. Stress myocardial perfusion imaging (MPI) may be considered for advanced cardiovascular risk assessment in asymptomatic adults with diabetes or asymptomatic adults with a strong family history of CHD or when previous risk assessment testing suggests a high risk of CHD, such as a coronary artery calcium (CAC) score of 400 or greater. (Level of Evidence: C)

Stress MPI testing is more sensitive than stress ECG testing alone but in clinical practice I see a very high rate of false positive stress MPI results. Stress MPI is also much more expensive than stress ECG testing and delivers significant radiation exposure to patients.

Thus if stress MPI is performed on all individuals with CAC>400 we are likely to generate lots of abnormal tests followed by lots of unnecessary down-stream testing.

Further support for the stress test approach comes from a 2013 report on appropriate use issued by an alphabet soup of cardiovascular professional organizations

Below is the incredibly complicated chart summarizing what tests can follow another abnormal test. Interestingly, in this chart the report consider it appropriate (A) to perform stress tests on individuals with calcium scores >100

Stress Testing-Costs and Downsides

The cynic in me has to point out that the average CAC score  for white males of 67 years is 98 and that of 68 years is 115. Thus, this algorithm has the potential to recommend stress testing be performed on half of all white males with no symptoms over the age of 67.

The costs of this approach would be astronomical.

This guideline supports stress ECG, stress MPI and stress echo as appropriate.  Stress MPI is considerably more expensive than stress ECG and carries substantial radiation burden. Stress echo in my experience,  if performed and read properly has the lowest incidence of false positives and is more appropriate therefore for screening asymptomatic individuals.

All this stress testing stands to benefit the various members of the alphabet soup above, especially those who read nuclear stress tests or stress echo or who do catheterizations with stents. (Full disclosure I am board certified in nuclear cardiology and echocardiography and read both stress MPI and stress echos. I don’t do catheterizations.)

It’s also important to point out that these appropriate usage criteria, with rare exceptions are based primarily on the expert opinion of the stakeholders who stand to benefit from the additional testing.

The unspoken third leg of the argument for stress testing is that once an abnormal stress test is found and the patient is noted to be in a higher risk category for events, therapy will be changed and this therapeutic intervention will improve outcomes.

This therapeutic intervention could be more intense management of risk factors for CAD but in most cardiologist’s and patient’s minds the next step is coronary angiography with the potential to stent blocked coronaries or to perform coronary bypass surgery.

Diabetic Patients With High CAC

Asymptomatic individuals with diabetes are recognized as intrinsically higher risk for cardiac events and commonly do not experience symptoms even with advanced CAD.

Thus, they are often the focus of more intense screening recommendations.

In 2017, The Imaging Council of the American College of Cardiology published their review of evidence regarding the use of noninvasive testing to stratify asymptomatic patients with diabetes with regard to to coronary heart disease, ultimately coming up with the algorithm below.

Their arguments were similar to Hecht’s for the general population:

Asymptomatic patients with diabetes who have high CAC scores have a high prevalence of inducible ischemia on stress imaging. In a prospective study, 48% of patients with diabetes with a CAC score of 400 had silent ischemia on SPECT imaging, and in those with a score of 1000, 71.4% had inducible ischemia . The majority of the defects were moderate to severe. Patients with diabetes with inducible ischemia have a higher annual death

Despite higher rates of ischemic stress test results in diabetics they did not recommend stress testing for all:

the data in DM suggest that routine screening with MPI of all asymptomatic patients is likely to have a low yield and have a limited effect on patient outcome. The yield of MPI can be improved by selecting a higher-risk group of patients with symptoms, peripheral vascular disease, CKD, an abnormal ECG, or a high CAC score (e.g., >400) (83,84). In such patients, intense medical therapy appears to retard progression of asymptomatic and symptomatic CAD (72).

Importantly, they noted the absence of evidence for revascularization in this population:

Whether coronary revascularization offers additive prognostic benefit to medical therapy when the ischemic burden exceeds any particular threshold is still unclear for the asymptomatic diabetic population.

The Argument Against Stress Testing

The argument for stress testing for high CAC rests on the assumption that identifying those individuals with significant ischemia due to tightly blocked coronary arteries can improve outcomes. This hypothesis has never been tested, let alone proven.

It may seem logical that those asymptomatic individuals with high risk CAC scores >400 and ischemia would benefit from an invasive strategy with coronary angiography followed by either stenting or bypass surgery but it is entirely possible that such an invasive strategy could cause more harm than good.

Harm comes from subjecting those individuals with abnormal stress tests to a potentially lethal procedure-cardiac catheterization.

David Schade, an endocrinologist, has opined persuasively on the inadvisability of either stress testing or cardiology referral in those with high CACS.

He correctly points out the limitations of coronary angiography which some cardiologists are very eager to perform

In many locations, stress testing is performed after referring the asymptomatic patient to a cardiologist. After a positive stress test, the next step is usually coronary angiography to identify obstructive lesions. A recent review of coronary angiography recommends caution in the use of this test because (1) the resolution of coronary angiography is low; (2) the obtained images are two dimensional, making it difficult to define the shape of the vessel; and (3) the assessment of obstruction does not include the presence of previously developed collateral vessels, which may provide adequate blood flow past the obstruction 

He quotes the USPSTF on the possible harm of this approach:

And he correctly points out that since the 2007 publication of the COURAGE trial we have known that catheterization followed by stenting does not improve outcomes in patients with stable CAD

Accord to the US Preventive Services Task Force: “The primary tangible harm of screening exercise tolerance testing is the potential for medical complications related to cardiac catheterization done to further evaluate a positive result. Coronary angiography is generally considered a safe procedure. Of all persons undergoing outpatient coronary angiography, however, an estimated 0.08% will die as a result of the procedure and 1.8% will experience a complication. Complications of coronary angiography include myocardial infarction, stroke, arrhythmia, dissection of the aorta and coronary artery, retroperitoneal bleeding, femoral artery aneurysm, renal dysfunction, and systemic infection”

In many locations, stress testing is performed after referring the asymptomatic patient to a cardiologist. After a positive stress test, the next step is usually coronary angiography to identify obstructive lesions. A recent review of coronary angiography recommends caution in the use of this test because (1) the resolution of coronary angiography is low; (2) the obtained images are two dimensional, making it difficult to define the shape of the vessel; and (3) the assessment of obstruction does not include the presence of previously developed collateral vessels, which may provide adequate blood flow past the obstruction 

Schade’s algorithm for management of a high CAC specifically recommends against referral to a cardiologist or performance of a stress test.

It emphasizes very intense management of risk factors with lifestyle changes and medical therapy with LDL goal <70.

As a cardiologist with a strong interest in prevention of atherosclerosis I agree with many of Schade’s points. I do, however, believe that high risk patients can benefit from seeing a cardiologist who is very focused on prevention of atherosclotic complications rather than performing procedures.

I don’t routinely recommend stress testing for my patients with high CAC but I have a low threshold for recommending stress testing in them based on worrisome symptoms, especially in those who are more sedentary or are diabetic.

A randomized trial comparing the outcomes of stress testing versus aggressive optimal medical therapy for the asymptomatic individual with high CAC is sorely needed. Until then, I remain

Skeptically Yours,

-ACP

 

A Set Of Peculiar Security Questions

The skeptical cardiologist has gotten used to answering security questions when establishing online accounts.

My answers to these questions are typically pretty obvious (to me) and easy to retrieve from my overwhelmed brain.

However, recently I was establishing an online account and encountered the following questions:

I was baffled by almost all of these and gave up.

For question #3 I might answer “to discourage online account activation.”

Unquestioningly Yours,

-ACP

N.B. Some of these questions are worthy of addition to the Proust Questionnaire

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

In Flight Medical Emergencies: This Doctor Is Now Ready To Heed The Call

In a previous post the skeptical cardiologist wrote about the reluctance  of doctors to “heed the call” , i.e., to respond to an in-flight medical emergency (IME) when the flight crew requests assistance from qualified medical professionals.

Only 20% of physicians in my (very unscientific) poll would respond to such requests.

I pointed out that:

“In 1998 Congress passed the Aviation Medical Assistance Act, which tries to protect medical Good Samaritans who heed an airplane call. The act protects physicians, nurses, physician assistants, state-qualified EMTs and paramedics:

“An individual shall not be liable for damages in any action brought in a Federal or State court arising out of the acts or omissions of the individual in providing or attempting to provide assistance in the case of an in-flight medical emergency unless the individual, while rendering such assistance, is guilty of gross negligence or willful misconduct.”

but I and other physicians  had concerns beyond medical liability, as I detailed in my post.

Physicians Who Prefer Not To Head The Call

At the time I wrote that piece, to be honest, I was in the camp of physicians who would prefer not to heed the call.

I tended to agree with Dr. Winocour on Larry David’s  Curb Your Enthusiasm who justifies his failure to respond in flight with two comments:

“Give it a minute. He’s gonna be fine.” and

“Have you ever been part of an emergency landing? Is that what you want, Larry? To spend the night in Lubbock, Texas, at a Days Inn with a $15 voucher from Cinnabon? Think about it.”

Although Winocour was correct that the vast majority of in-flight medical “emergencies” resolve without any specific intervention it is still helpful for a physician to attend on such patients and assess the situation.

And it is true that if he had attended on a patient with a serious non-transient medical problem he would suddenly find himself having to make an incredibly difficult and life-deciding decision on whether or not to  divert the plane or make an emergency landing with insufficient diagnostic tools and inadequate information.

But somebody has to make that call and the physician heeding the call will have the assistance of experts in the field on the ground.

Qualified Physicians Should Be Prepared To Heed The Call!

After pondering the issue for a few years and reading an excellent review on the topic in a recent JAMA I have changed my stance and am now completely ready (almost eager)  to heed the call.

Leslie Nielsen as Dr. Rumack in Airplane! He heeded the call.

In fact, I am currently writing this while en route from frigid and
snowy St. Louis to sunny and warm San Diego on a Southwest Airlines flight and I’m considering pre-identifying myself as a physician in case an IME develops. (The only thing stopping me is that it seems a little pretentious and likely unnecessary, perhaps if I just put wear my stethoscope constantly that will be enough.)

I have in my backpack several items that will assist me in handling cardiovascular emergencies should they arise:

  1. AliveCor Mobile ECG-With this and my iPhone I will be able to rapidly ascertain the stricken passengers heart rate and rhythm-crucial information to help diagnosis and proper treatment. (I also have my Apple Watch 4 for the same purpose.)
  2. Qardioarm BP cuff-Rapid, efficient assessment of BP without tubes, or wires.
  3. Stethoscope-a good one with which I can hear heart murmurs and lung sounds. Although the FAA-mandated emergency medical kit on board should have both a BP cuff and a stethoscope , I have no confidence they will be either accurate or functional.
  4. Sublingual nitroglycerin. The kit on the plane should have these  along with 325 mg aspirin tablets, IV atropine, and injectable glucose, epinephrine and lidocaine.
  5. An epinephrine auto-injector. For the stricken passenger who is suffering anaphylaxis from the mixed nuts being served across the aisle.

Should there actually be a cardiac arrest I’m completely up to date on Advanced Cardiac Life Support (ACLS) and CPR training and there should be an AED on board to defibrillate if appropriate.

I’ve also decided that despite my reluctance to bring attention to myself, it is highly likely that I will be the most qualified person to rapidly diagnose and treat any serious cardiovascular condition that arises on my flight.  As a doctor, I believe, I should be striving to provide assistance to those suffering whenever and wherever I can, be that in the air, on the sea, in the hospital or in the office.

Call-heedingly Yours,

-ACP

N.B. One (of many) of the newly-minted wife’s favorite Airplane! lines  comes from the doctor who heeded the call.

  • Rumack : You’d better tell the Captain we’ve got to land as soon as we can. This woman has to be gotten to a hospital.

    Elaine Dickinson : A hospital? What is it?

    Rumack : It’s a big building with patients, but that’s not important right now.

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