Little Evidence that Low-Salt Diet Prevents Heart Disease

salt shakers
Photo credit: Jorge Royan/Wikimedia

We know that people with high cholesterol have a higher risk for strokes and heart attacks than people with low cholesterol. So if a medicine lowers cholesterol it should also lower the frequency of strokes and heart attacks too. Right? Not necessarily. Estrogen lowers cholesterol and doesn’t lower stroke or heart attack risk. We also know that people with high blood pressure have a higher risk for strokes and heart attacks. Does that mean that a food that elevates blood pressure increases stroke and heart attack risk? Again, not necessarily.

The confusion here is a misunderstanding of the difference between clinical outcomes and intermediate outcomes. A clinical outcome is something that a patient notices herself and that impacts her life directly – like a stroke, a heart attack, or a bone fracture. An intermediate outcome is something that is measured by the doctor and that doesn’t cause symptoms directly – for example, elevated blood pressure, elevated cholesterol, or low bone density. Intermediate outcomes can be risk factors for clinical outcomes but shouldn’t be confused with them.

What does this have to do with salt?

Lots of evidence shows that eating more salt raises blood pressure, so doctors have always made the assumption that eating more salt also increases the risk of strokes and heart attacks. But as we’ve seen with estrogen and many other examples, guessing the effects on clinical outcomes from intermediate outcomes is frequently incorrect. In 2005 the USDA and Department of Health and Human Services wanted to revise their dietary recommendations for salt intake. Given the very little scientific evidence they had, what they did was both simple and presumptuous. They knew that 1,500 mg of sodium intake daily was the minimum needed for adequate nutrition. They also knew that at daily intake levels above 2,300 mg of sodium (which is about a teaspoon of salt) blood pressure begins to increase. So the US recommendations since 2005 have been that everyone should eat no more than 2,300 mg of sodium daily, and that people at very high risk of stroke and heart attack should ingest no more than 1,500 mg.

How are we doing? Well, on average Americans ingest 3,400 mg of sodium daily, well above the recommendations. A host of policy initiatives has been spawned by the recommendations in an effort to educate consumers, clarify food labels, and coerce restaurants to lower sodium.

But did anyone test the effects on the clinical endpoints?

The institute of Medicine (IOM) was commissioned to review all the studies relating to the health effects of sodium intake. Their report (which is over 150 pages) was released last week. A major conclusion of the IOM paper is that the quality of the current evidence linking salt to health outcomes is very poor. There are virtually no randomized studies and the rest of the studies suffer from important methodological flaws (like imprecisely measuring salt intake or using self-reported food diaries to estimate salt intake). The surprising and worrisome finding was that some of the randomized trials actually found worse outcomes with very low salt intakes. This isn’t as preposterous as it may sound. We have no solid understanding on salt’s effect on the body beyond that on blood pressure, so there could be many mechanisms that could explain worse cardiovascular outcomes with a very low salt diet.

The IOM endorsed the current belief that there is very likely a quantity of daily salt intake above which the risk of cardiovascular disease increases. The current evidence is simply insufficient to figure out what that limit is.

I’m always impressed when science comes up with the answer “We have no idea” because that’s very likely to be honest. Those who are more committed to enacting policy than to figuring out the truth are less likely to confess ignorance and to wait for better studies before making up their minds. The American Heart Association issued a press report criticizing the IOM paper and arguing essentially “But salt increases blood pressure!” which no one disputes.

So for now add me to the list of salt agnostics. I frequently ask patients to cut down on salt in the short term to avoid fluid retention, for example when traveling. But we should have the honesty to admit that in terms of long term outcomes we don’t know how much salt is too much.

And if you’re not going to eat that pickle, can I have it?

Learn more:

No Benefit Seen in Sharp Limits on Salt in Diet (New York Times)
Low-Salt Benefits Questioned (Wall Street Journal)
Is Eating Too Little Salt Risky? New Report Raises Questions (NPR)
Sodium Intake in Populations: Assessment of Evidence (Institute of Medicine)
Shaking the Salt Habit (American Heart Association)
New IOM report an incomplete review of sodium’s impact, says American Heart Association (American Heart Association Media Alert)

Merck Knows More about Zetia than They’re Telling Us (my post in 2007 explaining the difference between clinical outcomes and intermediate outcomes)

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Understanding Angelina

Angelina Jolie. Credit: George Biard / Wikipedia
Angelina Jolie. Credit: George Biard / Wikipedia

This week actress Angelina Jolie revealed in a New York Times op-ed that she underwent preventive double mastectomy. As would be expected of a personal revelation of such a well-known celebrity, it drew intense media attention. Her disclosure was brave and selfless and may save the lives of women in a similar situation, but is likely to be misunderstood by her myriad fans.

Jolie’s mother died at the age of 56 of cancer. (We are not told what kind of cancer.) This lead Jolie to pursue genetic testing which found that she had a harmful mutation in a gene called BRCA1. This mutation greatly increases her risk of breast and ovarian cancer. It was this finding that led her ultimately to choose preventive double mastectomy in an attempt to minimize her future breast cancer risk. Her description of her decision and ordeal is poignant. If you haven’t, please read it.

In this story of empowerment and survival, where is the potential for misunderstanding? Women are likely to misunderstand two issues – who should seek genetic testing for cancer causing mutations, and who should be considering preventive double mastectomies.

Let’s unpack the decision to get genetic testing first. Mutations in two genes called BRCA1 and BRCA2 are linked with very high risks of breast and ovarian cancer. But these mutations are quite rare in the general population, and these mutations are estimated to be responsible for only 5 to 10% of breast cancers and 10 to 15% of ovarian cancers. So genetic testing is not recommended for everyone. The National Cancer Institute lists the following groups of women as having a higher likelihood of a harmful BRCA1 or BRCA2 mutation.

  • For women who are not of Ashkenazi Jewish descent:
    • two first-degree relatives (mother, daughter, or sister) diagnosed with breast cancer, one of whom was diagnosed at age 50 or younger;
    • three or more first-degree or second-degree (grandmother or aunt) relatives diagnosed with breast cancer regardless of their age at diagnosis;
    • a combination of first- and second-degree relatives diagnosed with breast cancer and ovarian cancer (one cancer type per person);
    • a first-degree relative with cancer diagnosed in both breasts (bilateral breast cancer);
    • a combination of two or more first- or second-degree relatives diagnosed with ovarian cancer regardless of age at diagnosis;
    • a first- or second-degree relative diagnosed with both breast and ovarian cancer regardless of age at diagnosis; and
    • breast cancer diagnosed in a male relative.
  • For women of Ashkenazi Jewish descent:
    • any first-degree relative diagnosed with breast or ovarian cancer; and
    • two second-degree relatives on the same side of the family diagnosed with breast or ovarian cancer.

Women without these family history patterns are very unlikely of having a harmful BRCA1 or BRCA2 mutation. If you believe you might be in one of these groups the best way to get tested is to first consult a geneticist. A geneticist will evaluate your family and personal history and help you select the relevant genetic tests to order.

The other issue that women may misinterpret is Jolie’s decision to have a double mastectomy. This decision is entirely reasonable in a woman with a harmful BRCA1 or BRCA2 mutation, because of her very high lifetime risk of breast cancer. Unfortunately in recent years women have increasingly asked surgeons for mastectomies in situations in which mastectomies are not indicated. In an excellent and sobering article about how the drive to increase breast cancer awareness has unduly frightened hundreds of thousands of women, miscommunicated the benefits of mammograms, and failed to communicate the frequent harms of screening, Peggy Orenstein states that thousands of women consider double mastectomies after being diagnosed with low-grade breast cancer. In most women with localized breast cancer lumpectomies have been proven to be as effective as mastectomy in preventing recurrence, and the risk of breast cancer in the other breast is very low, so the decision to have a double mastectomy is driven purely by fear and a misunderstanding of the risk. It’s also important to know that bilateral mastectomies do not decrease the risk of breast cancer to zero because some breast tissue always remains. So preventive mastectomies are only helpful for women at very high risk of breast cancer, and even for them, preventive surgery isn’t the only option.

So I applaud Ms. Jolie for her courage in telling her story in the hopes that other high-risk women seek genetic counseling. And I hope that her fans understand that her decision and advice do not apply to the vast majority of women who are at average risk of breast cancer.

Learn more:

My Medical Choice (New York Times Op-Ed)
BRCA1 and BRCA2: Cancer Risk and Genetic Testing (National Cancer Institute)
Jolie’s Disclosure of Preventive Mastectomy Highlights Dilemma (New York Times)
Actress’s Move Shines Light on Preventive Mastectomy (Wall Street Journal)
Angelina Jolie, Breast Cancer Game-Changer (Wall Street Journal)
Our Feel-Good War on Breast Cancer (New York Times Magazine)

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Suicide Rate Among Baby Boomers Increases Sharply

Golden Gate Bridge
The Golden Gate Bridge is the second most common site for suicide in the world. Photo credit: Wikimedia Commons

Every primary care doctor has had the experience of listening to a very depressed patient explain that things are hopeless, that chronic medical problems or financial setbacks or family conflicts have pushed the patient past his ability to cope, that he can’t imagine how things could ever get better, that he would be better off dead.

Unfortunately, suicide in the United States is increasingly common. An article in the CDC’s Morbidity and Mortality Weekly Report earlier this month reviewed the suicide statistics between 1999 and 2010. The number of suicides increased by almost a third over that decade, from 29,181 in 1999 to 38,364 in 2010. In 2009 the numbers of suicides surpassed the deaths due to motor vehicle crashes for the first time. Though previously suicide was a problem predominantly among teens and senior citizens, the increase over the last decade has been largely in middle-aged adults. This trend is worrisome to public health officials since current attempts at suicide prevention are not targeted to working age adults.

The cause of this increase in suicides isn’t known. In an attached editorial CDC officials speculate about three possible causes. The recent economic downturn certainly may be contributing, as previous difficult economic times have correlated with increases in suicide rates. Another possible cause may relate to the generation of baby boomers themselves. Statisticians call this a cohort effect. Baby boomers had a higher rate of suicide in their teens than prior generations. Perhaps something unique about baby boomers and the times in which they came of age increases their risk of suicide. They certainly were disproportionately involved in the idealism (and radicalism) of the 1960s. It is certainly possible that many of them expected to build a very different world than the one they find themselves in. Finally, prescription pain medications are being prescribed and misused in unprecedented quantities. The authors speculate that the widespread addiction to opiates might be contributing to the increasing frequency of suicide.

Two years ago Freakonomics Radio, the series of podcasts inspired by the bestselling economics book, had a fascinating podcast about suicide. When you have an hour, I highly recommend listening. The podcast mentions that after media reports of suicide, especially in which the victim is famous or portrayed in a positive or sympathetic light, the frequency of suicides increases. Apparently even songs about suicide have been known to trigger “contagions” of suicide. So the media slowly learned to highlight in their stories the grief of loved ones, the disfigurement of the victim’s body, the missed opportunities to get help, in an attempt to make suicide less inviting to those who are contemplating it.

So with that in mind, allow me to offer a few personal observations gleaned from caring for many depressed patients during 15 years of practice.

  • Depression is treatable. I’ve seen many hopelessly suicidal, miserably sad patients get better.
  • Hopelessness and pessimism are a symptom of the depression, not a rational assessment of the situation. I’ve cared for people with catastrophic health problems and terrible family and financial situations, but no depression. They didn’t want to kill themselves. Depression alters judgment and makes a better future seem impossible.
  • Suicide causes permanent grief to loved ones.
  • All you have to do is postpone suicide for now, and get help. That doesn’t limit your options later. You can always think about suicide again in the future.

So while every primary care doctor has cared for a patient at the depths of depression, we’ve all also seen them months later after the medications and the talk therapy have started to work. They may still be suffering, but they’re glad they’re alive and are relieved that they didn’t do anything irreversible before. Perhaps now that we know about this trend we can focus more attention on depressed baby boomers and convince them that hope is not lost.

Get help:

National Suicide Prevention Lifeline
(800)273-8255
(800)273-TALK

Learn more:

Suicide Rates Rise Sharply in U.S. (New York Times)
Suicides Soar in Past Decade (Wall Street Journal)
Suicide Rate Climbs For Middle-Aged Americans (NPR Shots)
Economic downturn cited as suicide rate jumps for those between 35 and 64 (Daily News)
Suicide Among Adults Aged 35–64 Years — United States, 1999–2010 (Morbidity and Mortality Weekly Report)
The Suicide Paradox (Freakonomics Radio podcast)

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Avian Flu (N7N9) Makes Leap from Bird to Man

H7N9 Avian Flu Virus
Electron micrograph of H7N9 influenza virus. Credit: CDC

Do you remember the H1N1 swine flu that made tens of millions sick and killed thousands of people in 2009? Well, one if its cousins, a bird flu with the name H7N9, is causing some death and consternation in China.

This strain has long been circulating among birds, but since earlier this year people have become ill with this respiratory virus, all so far in China. This week’s issue of the New England Journal of Medicine (NEJM) published a review of the public health findings thus far.

The review stated that up to now 82 people have been confirmed to have H7N9 in 6 different regions of China. Most of them were extremely ill, but that is largely because of the way in which they were identified – patients with severe respiratory illness were tested for the virus. Of these 82 patients, 17 have died (21%) and 60 remain critically ill. The incubation period ranged from 1 to 10 days, and those who died were ill for a median of 11 days.

Four of the patients were poultry workers and 77% had known exposure to live animals, mostly chickens. This suggests that the majority of the cases are due to transmission from birds to humans. There were no confirmed cases of human to human transmission but in two families human to human transmission could not be ruled out.

The concern is that eventually, through random mutations, H7N9 will get better at human to human transmission. Then, as in the swine flu epidemic of 2009, since the entire human population has never been exposed to H7N9, we will be a very large non-immune target. Like the first spark in a forest that hasn’t burned in many decades, very rapid spread would be likely.

Yesterday the first case in Taiwan was reported, so the virus has spilled out of mainland China.

Is it time to panic? No. Not unless you frequent live poultry markets in China. H7N9 has not been detected in people or birds in the US. American health officials are keeping a close eye on the spread of the virus. They are trying to determine how many people have mild disease from H7N9 to better calculate how lethal it is. (People with mild illness may not be seeking medical attention. If hundreds of people have had undiagnosed mild illness then the virus is much less deadly than if the only people who got the virus are the 80-or-so we know about.) They are also waiting for the first confirmed transmission from person to person. That’s when all the measures that we saw in 2009 will be revisited – a new vaccine, reminders for people to stay home when sick, and despite official reassurances everybody freaking out.

Learn more:

Preliminary Report: Epidemiology of the Avian Influenza A (H7N9) Outbreak in China (NEJM)
Avian Influenza A (H7N9) Virus (Centers for Disease Control and Prevention)
China’s H7N9 bird flu death toll likely to rise (Los Angeles Times)
China Reports Three New H7N9 Bird Flu Cases; Jiangxi Has 1st Suspected Illness (Forbes)

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The American College of Physicians Releases Prostate Screening Guidelines

Photo credit: Graham Colm / Wikimedia Commons
Photo credit: Graham Colm / Wikimedia Commons

My regular readers have been following the controversy about prostate cancer screening for some time. The controversy boils down to the following question. Should healthy men be routinely tested for prostate cancer? The most recent chapter in the controversy was written last year when the US Preventive Services Task Force (USPSTF) recommended against prostate cancer screening for men of any age. If this is news to you, or sounds absolutely preposterous, follow the previous link to read about the rationale of the USPSTF recommendation. The bottom line is that the benefits of screening have been shown to be very small or nonexistent, while the harms are proven and significant.

But where does that leave physicians? If you’re a man between 50 and 70 and you’ve seen me for an annual exam in the last year, you know that the recommendations have led to very difficult discussions without very clear guidance. Many men are used to annual screening and are distressed at the idea that suddenly we would do nothing to detect a potential cancer. Younger healthier men are especially puzzled about what to do since they would be most likely to die from an undiagnosed prostate cancer, though they would be least likely to develop prostate cancer.

To clarify our current understanding, and provide direction that is somewhat more useful to primary care physicians, last week the American College of Physicians released guidance statements that crystallize their recommendations.

Guidance Statement 1: ACP recommends that clinicians inform men between the age of 50 and 69 years about the limited potential benefits and substantial harms of screening for prostate cancer. ACP recommends that clinicians base the decision to screen for prostate cancer using the prostate-specific antigen test on the risk for prostate cancer, a discussion of the benefits and harms of screening, the patient’s general health and life expectancy, and patient preferences. ACP recommends that clinicians should not screen for prostate cancer using the prostate-specific antigen test in patients who do not express a clear preference for screening.

Guidance Statement 2: ACP recommends that clinicians should not screen for prostate cancer using the prostate-specific antigen test in average-risk men under the age of 50 years, men over the age of 69 years, or men with a life expectancy of less than 10 to 15 years.

I find this very helpful, and it will help guide my conversations with men who are 50 to 69. It incorporates our current understanding while acknowledging that patients have unique values, anxieties, and preferences that should inform their care. If you’re a man between 50 and 69 give Guidance Statement 1 a close reading and tell your doctor what you think. If you love a man of that age, send him this post.

Learn more:

Screening for Prostate Cancer: A Guidance Statement From the Clinical Guidelines Committee of the American College of Physicians (Annals of Internal Medicine)
Doctors group questions prostate cancer screening (Reuters)

Some of my previous posts about prostate cancer:

Many with Prostate Cancer Do Not Benefit From Surgery
Why I Won’t Have a PSA Test When I Turn 50

Tangential Miscellany

The images and stories from Boston are terrifying and heartbreaking. I believe there is a fascinating story to be written about the medical aspects of the minutes, hours, and days after the explosions. I hope we eventually read that story. By all accounts the first responders, the emergency department staffs, and the surgical teams did extraordinary work very quickly. The newspaper stories suggest that many of the wounded have survived life-threatening injuries because of the fast and organized work of many dedicated professionals. I know that all of you join me in wishing physical and emotional recovery to the injured, calm and focus to the medical teams, and deep condolences to the bereaved.

This Sunday is Ciclavia, a citywide event in which 15 miles of streets are closed to traffic and open for strolling, biking, and exploring the city. It’s a perfect opportunity to demonstrate that we will still gather in large groups, have fun, get some exercise, and wear Red Sox hats.

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ACP Potpourri

Image credit: ACP

Greetings from San Francisco, where I am attending the American College of Physicians 2013 Scientific Program, their annual conference covering the latest progress in internal medicine. Though the conference is obviously geared for physicians, I’ve compiled below a half dozen points from the various lectures that I think might be of interest to patients. Feel free to skim, and if you want to learn more about any point, follow the links.

  • Ezekiel Emanuel, MD, PhD, gave the keynote address. Those unfamiliar with his biography and his work on healthcare reform can learn more by following the link. His speech highlighted the many changes anticipated in healthcare in the next few years and was intended to reassure us that physicians will be leaders in the transformation of American medicine. The specifics he discussed, however, were largely centrally planned policy directives over which physicians will have little influence. This makes me suspect that physicians will be passengers, not drivers, in the coming revolution.
  • More than one lecture mentioned the very important study a year ago that demonstrated that patients with sinus infections treated with antibiotics don’t improve any faster than on placebo. A very large fraction of all antibiotic prescriptions are for sinus infection, and as my regular readers know antibiotic use increases the risk of bacterial resistance and of Clostridium difficile infection. The latest recommendations for acute sinusitis is to use only nasal decongestants and pain relievers for 10 days after symptom onset. The vast majority of patients improve with only symptomatic treatment, either because they had a viral infection (for which antibiotics are ineffective) or because the nasal decongestants allowed drainage of the sinuses, allowing the patients’ immune system to kill the few remaining bacteria. Only patients who have not improved in 10 days should be prescribed antibiotics. This may be a difficult change both for patients and physicians. I know that despite my best efforts I am occasionally pressured by (well-meaning) patients to prescribe unnecessary antibiotics. I hope I can educate patients about this in a way that does not frustrate them.
  • The new medications for obesity were discussed by several speakers. Belviq (lorcaserin) and Qsymia (phentermine/topiramate) will be available by prescription soon for treatment of obesity. The difference in attitudes towards these medications of the different speakers was fascinating. The professor who was a general internist was hesitant to recommend them based on the absence of long-term safety data and the terrible safety track-records of prior obesity medications that were withdrawn from the market. The obesity specialist, on the other hand, seemed quite enthusiastic to prescribe these medications given how empty our armamentarium is for this serious problem. (I side with the general internist.)
  • An important study last year showed that in patients with blood clots in their legs who are treated with a blood thinner (warfarin, Coumadin) for 6 to 18 months should continue taking aspirin thereafter to prevent a recurrent clot.
  • Women with normal bone density or mild osteopenia can wait 10 to 15 years before next rechecking their bone density, with very little risk of missing their transition to osteoporosis. I really should be recommending bone density testing less frequently in these women.
  • More than one lecturer on various different topics mentioned Choosing Wisely, the partnership between the American Board of Internal Medicine and various physician specialty organizations dedicated to educating physicians and patients about tests and treatments that have no benefits. Speakers about topics from ranging from preoperative chest X rays to CT scans for acute sinusitis showed us the studies proving that the tests are worthless and mentioned that Choosing Wisely is trying to get physicians to stop ordering such tests. I remain supportive of the program’s goals but pessimistic about its effectiveness. This may be effective if enough patients become well-informed, but hoping that thousands of physicians will behave against their interests by ceasing to order high-price low-benefit services is unrealistic. This may be another reason for patients to choose physicians who have no incentive (or disincentive) to recommend any specific test or treatment.

Finally, I was pleasantly surprised to find that many of the studies that were highlighted by the professors were ones I wrote about over the year. Reviewing the literature has helped me understand the studies, and composing the posts in non-technical language has helped me remember the key points. There is no better way to learn than to teach. Thank you for reading.

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Supplementing Mediterranean Diet with Olive Oil or Nuts Decreases Stroke Risk

Olive Oyl did not participate in this study and did not return my calls for comment. Image credit: Wikimedia Commons/public domain

What is a Mediterranean diet? I had always believed that it involves eating shawarma three times a day while sitting on a beach in Tel Aviv, just because that’s my diet when I visit the Mediterranean. I was astounded to learn that this is not the case. A Mediterranean diet includes a lot of fruits, nuts, vegetables, olive oil, and cereals. It includes moderate intake of fish and poultry, and very little dairy, red meat, and sweets. Wine is included in moderation and consumed with meals.

Like the low-carbohydrate (Atkins) diet and the low-fat diet, the Mediterranean diet has passionate adherents and advocates. A debate between proponents of different diets quickly resembles one between zealots of different religions – there is much heat but little light. That’s because virtually no high-quality studies have directly compared one diet to another. So in the face of weak data, each camp highlights the data that confirms their bias and disregards the rest.

A study published in this week’s issue of The New England Journal of Medicine (NEJM) tried to compare a Mediterranean diet to a low-fat diet. The study took place in Spain and randomized over 7,000 people who did not have cardiovascular disease at the start of the study but had risk factors for cardiovascular disease, like diabetes or high cholesterol. The people were randomized into three groups. The first group was instructed to follow a Mediterranean diet and told to add about four tablespoons of extra-virgin olive oil (which was provided by the study) to their diet daily. The second group was also instructed to follow a Mediterranean diet. They were instructed to add about a quarter cup of mixed nuts (also provided) to their diet daily. The third group was instructed to follow a low-fat diet.

The three groups were followed for an average of 5 years. Strokes, heart attacks, and other episodes of cardiovascular badness were tallied.

The three groups had similar numbers of heart attacks, but the two groups following the Mediterranean diet had significantly fewer strokes than the group instructed to follow the low-fat diet. The statistics suggest that for every 60 people in one of the Mediterranean diet groups instead of the low-fat diet group one stroke is prevented every five years. That’s pretty impressive, and is better than some medications used for stroke prevention.

So does this mean that a Mediterranean diet is better at stroke prevention than a low-fat diet? Not at all. As an accompanying editorial makes clear, what is important is what the three groups actually ate, not what they were supposed to eat. The first two groups were pretty good at keeping a Mediterranean diet, but the third group which was supposed to eat a low-fat diet, didn’t  Most of the people in the third group, despite being instructed to eat a low-fat diet, ate pretty close to a Mediterranean diet, which is what they were eating before the study. That makes sense. Spain is Mediterranean, and it’s very hard to change people’s eating habits.

So this study doesn’t teach us anything about the benefits of a Mediterranean diet, but you wouldn’t know that from the headlines in the popular press coverage (links below). This study taught us much more about how ineffective it is to instruct people to change what they eat, and much less about whether one kind of diet is healthier than another.

This study does suggest that in people eating a Mediterranean diet, adding olive oil or mixed nuts decreases stroke risk, which in itself is very interesting. Does that mean that olive oil and mixed nuts might prevent strokes in the rest of us? Maybe. I certainly wouldn’t object to my patients adding nuts and olive oil to their diet, and I’m busily trying to figure out how to order that with my next shawarma.

Learn more:

Olive Oil Diet Curbs Strokes (Wall Street Journal)
Mediterranean Diet Shown to Ward Off Heart Attack and Stroke (New York Times)
Mediterranean diet over low fat? Well, at least it’s more fun (Los Angeles Times opinion)
Primary Prevention of Cardiovascular Disease with a Mediterranean Diet (NEJM article)
Did the PREDIMED Trial Test a Mediterranean Diet? (NEJM editorial)

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A New Hope for Hepatitis C Infection

The Hepatitis C virus is what scientists call very small. Here is an electron micrograph of one. The scale bar is 50 nanometers. Photo credit: Wikimedia/Rockefeller University

Hepatitis C is a viral infection that is usually spread through contact with infected blood. Prior to 1992, when testing of donated blood and organs became commonplace, many people were infected through blood transfusion and organ transplants. Now the most common method of infection is the sharing of needles or other equipment for injecting drugs. About 3.2 million people are estimated to have chronic hepatitis C infection in the U.S. Over decades, chronic infection can lead to liver failure and liver cancer. Hepatitis C is the leading indication for liver transplantation in the U.S. There is currently no vaccine.

Current medications for hepatitis C have some serious side effects and are sometimes only effective transiently, because the virus can develop resistance to the anti-viral medications. Current medications work by blocking the function of one of the virus’s components, so mutations in the virus can alter that component making the medicine ineffective.

A novel family of medicines has focused on targeting a part of the healthy liver cell that the virus uses to replicate. A specific kind of molecule called microRNA which is present in normal liver cells is required to bind to part of the hepatitis C for infection and viral replication to occur. This new family of medicines, called microRNA inhibitors, bind microRNA and prevent them from binding to hepatitis C.

A study published in this week’s New England of Medicine (NEJM) tested the effect of miravirsen, a microRNA inhibitor, in hepatitis C patients. This was a preliminary study designed to find the short-term effects on a small number of patients. Only 36 patients were enrolled in the study and they received five weekly injections of various doses of miraversen or of placebo.

The results were encouraging. The patients receiving miraversen had a large drop in the amount of hepatitis C virus detected in their blood. This effect lasted after the miraversen treatment was stopped. In a few patients the amount of hepatitis C in their blood fell below the limits of detection. There were no serious side effects, and none of the virus obtained from patients showed mutations suggesting resistance to the new drug.

Larger and more prolonged studies are needed before the miraversen is generally available, but besides the potential hope for hepatitis C patients, microRNA inhibitors may find utility in a number of other diseases.

Learn more:

A new drug shows promise of hepatitis C cure (Booster Shots, LA Times’ health blog)
‘Sponge’ Drug Shows Promise For Treating Hepatitis C (Shots, NPR’s Health blog)
Treatment of HCV Infection by Targeting MicroRNA (NEJM article)
Micromanaging Hepatitis C Virus (NEJM editorial)
Hepatitis C Information for the Public (Centers for Disease Control and Prevention)

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Azithromycin Might Kill You, but That’s Not Why You Shouldn’t Take It

This week the FDA issued a warning about the antibiotic azithromycin (Zithromax). The media stories have some patients terrified and some of them are calling me convinced that azithromycin is poison, a reliable agent for suicide.

What’s the hubbub about?

Azithromycin is in a family of antibiotics called macrolides, which also includes erythromycin and clarithromycin (Biaxin). Erythromycin and clarithromycin have long been known to very rarely cause fatal abnormal heart rhythms. It was thought that azithromycin didn’t have this rare side effect.

In May of last year the New England Journal of Medicine (NEJM) published a study that tried to confirm this. The study compared rates of sudden death while taking a course of azithromycin to the risk while taking amoxicillin, ciprofloxacin, levofloxacin, or no antibiotic. The study was not randomized. It simply matched hundreds of thousands of antibiotic prescriptions to death certificates.

The study found a tiny increased risk in patients taking azithromycin. How tiny? Compared to taking amoxicillin, taking azithromycin contributed 47 additional cardiovascular deaths per 1 million antibiotic courses. That’s one extra death per 21,276 courses. If you took 5-day azithromycin courses continuously, it would take 291 years to take that many courses of antibiotics. That’s a much slower way to die than, say, hemlock.

All patients did not have the same risk of having a fatal heart rhythm abnormality. Older patients, patients taking medications for heart rhythm abnormalities, and patients with heart disease, certain EKG abnormalities, and certain electrolyte abnormalities were at greater risk of this side effect. The patients at highest risk face one additional death every 4,100 courses of antibiotics, while those at lowest risk have one additional death every 110,000. These are very, very small risks.

So doctors should try to avoid all macrolides in high risk patients. But patients should probably forget the whole thing and avoid azithromycin for a different reason.

The reason you should avoid azithromycin is the same as the reason you should avoid all antibiotics. The risk of Clostridium difficile infection and the risk of antibiotic resistance is much greater than the miniscule risk of a fatal rhythm abnormality. That’s what should be scaring you about antibiotics. This is especially true of azithromycin because its convenient 5-day course, the Z Pack, has become a household name and patients ask for it even when antibiotics are very unlikely to help. It is very likely that the last Z Pack you took was for a cold, or for acute bronchitis, or for an early sinus infection, all of which resolve without antibiotics.

It would be a sad irony if we needed the irrational fear of extremely rare side effects to counter the irrational exuberance that patients have for unnecessary antibiotics. I hope instead that educated patients armed with reliable information will make good decisions.

Learn more:

F.D.A. Raises Heart Alert on Antibiotic in Wide Use (New York Times)
FDA Strengthens Warnings On Pfizer Antibiotic (Wall Street Journal)
FDA says Zithromax can cause fatal irregular heart rhythm (Reuters)
Azithromycin (Zithromax or Zmax) and the risk of potentially fatal heart rhythms (FDA Drug Safety Communication)
Azithromycin and the Risk of Cardiovascular Death (NEJM, May 2012)

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Normal Test Results are Often Not Reassuring

A CT scanner. Not a good test for anxiety. Credit: Wikimedia Commons/1weezie23

Every primary care doctor has been faced with this situation. A patient reports vague symptoms and is very worried that they are a sign of a catastrophic illness. The symptoms aren’t even slightly suggestive of the disease the patient is worried about, but the patient’s neighbor’s brother-in-law was just diagnosed with the same disease, and so the patient is pretty sure that he has it too. The doctor is not at all suspicious that the patient has this disease. The doctor believes that the patient is simply anxious, and that his symptoms are either caused by his anxiety or are normal bodily sensations that are being magnified and given lots of attention because of the news about the neighbor’s brother-in-law.

What can the doctor do? One option is to order a test – a CT, a MRI, blood tests, whatever would rule out the specific disease the patient is worried about. The doctor is not ordering the test because he is actually curious about the results. He thinks the probability of an abnormal result is extremely low. He is ordering the test simply in the hopes that a normal result will reassure the patient, decrease the anxiety, and maybe even lead to the resolution of the symptoms by letting the patient focus on something else.

The temptation to order the test is pretty great (especially if the doctor owns the testing equipment). But will it work? Will the normal test result fix the problem?

A study published this week in JAMA Internal Medicine attempted to answer that question. Researchers compiled all previous published randomized trials that assessed diagnostic testing done for symptoms that were unlikely to represent serious illness. They found that on average the patients’ reported anxiety and symptom severity did not decrease after the result was normal.

So when the disease being investigated is very unlikely, ordering a test just to reassure a patient doesn’t actually reassure the patient.

It might be more effective to take the time to understand the cause of the anxiety. Perhaps the patient is actually very close to the neighbor’s brother-in-law and is himself devastated by the bad news and simply needs to express how sad he is for his friend. Or perhaps he has health anxiety (hypochondriasis) and has been to a dozen doctors in the last six months with different symptoms getting myriad normal tests. The former just needs some sympathetic listening. The latter needs cognitive behavioral therapy. Neither benefit from diagnostic testing.

Another reason to avoid testing for a disease that is very unlikely in a given patient has to do with math. I wrote last year that screening for most diseases is not helpful. One of the reasons is that no test is perfect. If the likelihood that the disease is present is extremely small, an abnormal test is more likely to be caused by an test error than by the disease being present. So testing patients that are almost certainly healthy raises the possibility of false positives due to test errors. That won’t reassure anyone and will likely lead to more tests to pursue the spurious abnormal result.

Doctors need to learn to say to patients “That doesn’t sound worrisome. Let’s just keep an eye on it.” without being dismissive. Patients need to learn that a system that pays more for testing than listening will deliver more testing than listening.

Learn more:

In many patients, diagnostic testing isn’t reassuring after all (LA Times)
‘Worried Well’ Often Ignore Negative Test Results: Study (US News)
Reassurance After Diagnostic Testing With a Low Pretest Probability of Serious Disease (JAMA Internal Medicine)
Doctor, Test Me for Everything (My post from last year explaining why some screening tests are harmful)
It’s Not All in Your Head: How Worrying about Your Health Could Be Making You Sick and What You Can Do about it (A very helpful and authoritative book for patients with health anxiety)

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