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Tuesday, July 26, 2016

The "Yearly Physical"


"I'm going to the doctor next week for my yearly physical."

So normal. Of course you are. Everyone should do that.

But the concept of a yearly examination of one's whole body to see if everything checks out fine is a relatively new invention and whether or not it is necessary is a very controversial question.

I just read an article by Abraham Verghese, an internist and champion of physical diagnosis, professor at Stanford University, inspired writer, about the history of the physical exam. The idea that physicians could know more about a person than he or she could know about him or herself has only gained traction in the last century and comes partly from the invention of gadgets such as the stethoscope, the reflex hammer and the blood pressure cuff which reveal truths only to those of us skilled in their use. Enthusiasm for these has waned a bit as we have become enamored of our ability to see the shadows made by bones and such during an onslaught of electrons (x-rays), or the ability to check the levels of molecules and minerals in the fluids of our bodies, among other technological miracles. This evolution which takes us away from the bedside has also made us less confident in and also less dependent on the information we get by physically examining our patients.

We love what we can measure and correlate, and the physical exam is part of that process. If we can feel an enlarged spleen or liver, that is correlated with certain disease states, but certainly not always. If we can feel lumps in the breasts, testicles or thyroid, there may be something life threatening going on. Or not.

As doctors, we are trained in the nuances of the physical exam. I learned how to examine every orifice and surface, looking for specific abnormalities, and then developed skills over many years in understanding the wide variation in normal people. My physical exam is a conversation with my patient's body which happens simultaneously with a verbal conversation, which in itself is a kind of physical examination. How a person speaks, what interests them, how they follow the conversation are part of the neurological and psychiatric examination. As the physical exam unfolds, my understanding of a patient and my relationship with him or her deepens.

Does a physical exam save lives? I'm not sure. The definitive study will never be done. Only a small subset of what we do at the time of a physical exam has been rigorously studied and found to be of benefit. What a physical exam should entail has never been adequately worked out and there is no consensus. A pelvic and rectal exam, synonymous for some people with a "complete physical" have not been shown to have value in a patient with no symptoms in those areas. These and other parts of a "routine physical" may lead to overdiagnosis: finding something wrong that leads to more testing or treatment that does not improve or lengthen life. Nevertheless, it seems likely that a physical exam, done well and mindfully, is substantially valuable.

If it is valuable, shouldn't we all be getting one, yearly at least? Not necessarily. Plenty of people are healthy and will remain healthy without a doctor doing anything at all to them. "Health checks" were studied by the Cochrane Collaboration and found not to improve morbidity or mortality. There are a few things that would be good to check if you are feeling healthy, just to make sure all is well, though.  It would be good to measure blood pressure  or screen for HIV or hepatitis C for people at risk. If a patient somehow hasn't heard that it is unhealthy to smoke and be inactive and morbidly obese, ride a motorcycle without a helmet or drink and drive, it may make sense to impart this wisdom.

Medicare does not cover a general physical in the sense that most people think of it. What it does cover is a "Welcome to Medicare Physical" right after becoming insured under Medicare, which involves some screening that is important for determining risks and needs, and a yearly "Wellness Visit" which involves only vital signs and some screening tests along with advice on what is presently being recommended, stuff like mammograms, pap smears and colonoscopies. Patients are often put off by this because they don't like scripted interactions with their doctors, and doctors are put off by it because we have usually not memorized the script and some of us are not sure we agree with it.

Is a physical exam a good idea then? And should it be performed yearly on everyone? I, personally, would prefer that I have a chance to have unstructured time to physically examine and interview my patients yearly, in other words to do a physical. I would like them also to get information about what the evidence says about various screening tests and I would like that to be easily accessible in the medical record, but I don't necessarily feel strongly about being the person to offer that information. Perhaps a nurse or a health educator could do that better. I recognize that insurance companies may not cover a complete exam for a person who is healthy.  For this reason, a physical exam may need to be scheduled as a prolonged visit to discuss multiple health issues. Taken as a whole, and not because it is based in scientific evidence, I favor the physical exam. I also would completely forgive anyone who preferred to skip it.

Tuesday, July 19, 2016

Preventing Cervical Cancer in Tanzania

I visited Tanzania again this summer, once again helping a group of amazing University of California, Irvine medical students with their summer not-a-vacation trip to teach bedside ultrasound and do other research projects. 
One of the projects this year sprung out of a request by a doctor we have worked with on Ukerewe Island. The island he serves is rural, primarily supported by fishing, and has a high rate of sexually transmitted diseases due to fishermen visiting prostitutes on the mainland and bringing home infections to their wives and girlfriends. This translates to high rates of HIV infection, pelvic inflammatory disease and the spectrum of disease caused by human papillomavirus (HPV). HPV can cause genital warts, which are only mildly distressing, but it can also set in motion cellular changes of the cervix that can lead to cervical cancer. Tanzania has a distressingly high incidence and death rate from cervical cancer and this Tanzanian physician asked one of the students if we could do a project that would help reduce cervical cancer.

The high mortality and incidence of cervical cancer in sub-Saharan Africa can be (and has been) addressed in many ways. Primary prevention would involve using condoms or maintaining celibacy or reliable monogamy. We have a vaccine now that can prevent persistent infection, but it is still very expensive and not used much in resource poor countries like Tanzania. Pap testing is the method we use in the US to prevent cervical cancer, and its use is widespread and effective here. It involves taking a sample of the cells of the cervix during a speculum exam, sending this to a pathologist for evaluation, and repeating that test at regular intervals. Abnormal pap tests are reported to the patient who is notified to return for further testing and eventually removal of the infected tissue if it persists. The abnormal tissue is visualized by applying acetic acid to the skin of the cervix, then using a cervical microscope or colposcope to either biopsy, cut or freeze away abnormal tissue. In most of Africa this is not even vaguely practical since women go to the doctor infrequently and speculum exams are not often performed. It is not always practical to contact people by phone, and they often come from far enough away that returning for multiple visits to deal with an abnormal pap is not likely to happen. In addition, were physicians to start performing regular pap testing, there are not enough pathologists to process the specimens.

About 10 years ago I read an article in one of the large medical journals which described an abbreviated screening test for HPV infection in which vinegar (acetic acid) was applied to the cervix, abnormal areas that looked HPV infected were identified with the naked eye and those areas were simply frozen, destroying the infected and precancerous tissue. This sounded amazing. Since then this procedure has become well accepted, though certainly not universally available, to people living in many African countries. The World Health Organization has studied it and pronounced it to be practical and recommends it for resource poor settings.

The students heard about an organization, CureCervicalCancer, which teaches healthcare workers visual inspection with acetic acid (VIA) and supplies a gun which can deliver compressed carbon dioxide (available in poor countries because it is used to make soda pop) to the infected tissue of the cervix, to freeze it off.

This year several people affiliated with Cure Cervical Cancer came to Tanzania with us, trained Tanzanian MD and non-MD healthcare workers to perform visual inspection and cryotherapy and gave them supplies they would need to make the service ongoing.

The idea of being able to provide that kind of immediate and practical service was very exciting. I just thought it wouldn't work. Doctors and nurses in Tanzania are so overworked that I doubted they would come for a few days to learn a new technique. I also thought that a pelvic exam using a speculum would be a VERY hard sell for women who have never had a pelvic exam, especially since they would be feeling fine. I thought that the doctors wouldn't have time to continue to do these exams after we left. It turns out I was wrong: health care workers were enthusiastic and attended the trainings and women lined up for testing. 

The first day we had fewer patients than the leaders felt was acceptable, about 60 patients total I think. So the students who knew Tanzania from previous trips made flyers which they handed out, used their large word of mouth network and finally hired guy in a truck with a loud speaker to drive around the streets advertising the free clinic. The next two days doubled or even tripled the number of patients screened! Several cases of HPV infection were seen and treated and a few early cervical cancers were identified and referred for likely surgery.

This project may persist. They were able to train people from the city of Mwanza as well as Ukerewe Island and they promise to continue to do screening after we leave, free of charge. We shall see. There is some kind of audit planned for 6 months out. Clearly more nurses and doctors need to be trained to do this. This is clearly the right kind of screening to do in this setting and may reduce the burden of cervical cancer. In our screening clinic the host hospital also offered free HIV screening which was fantastic since treatment of HIV in Tanzania is free. Cervical cancer is more common and more aggressive in HIV infected women, so combining the screenings is really powerful.

I think this will help. I do have some reservations, though. In the US, 80% of people will be infected with HPV during their lifetimes, and the vast majority will kick it and have no ill effect. At any one time, I've read, 10% of women will have HPV infections. Only a fraction of the types of HPV that are out there are able to cause cervical cancer. The point here is that all HPV infection does not necessarily need treatment. We don't have evidence yet that VIA with cryotherapy saves lives, though it seems likely that it will and there have been mathematical models that evaluate this. VIA is, though, a sustainable method to treat HPV infection early and thus to prevent late sequelae including cancer  Clearly real prevention of infection would be the most valuable intervention in prevention of cervical cancer. This could be by vaccination, if the vaccine were affordable, or use of condoms to prevent transmission of infection.  More important even than that would be changes that allow women to have more control of what happens to them sexually. This will require improved education and economic opportunities so that women have value in the society outside of their roles as mates and mothers.




Sunday, July 10, 2016

My thyroid nodule

About 4 years ago I was examining my neck and discovered a nodule in the right side of my thyroid gland. I was examining my neck because I very rarely see a doctor and figured that I should at least cursorily examine myself to see if I could find anything of interest. My heart sounded fine, my lungs were excellent, weight was just right, pulse was nice and low, liver and spleen were fine, skin was slightly sun damaged but basically OK, blood pressure was a tad high and there was a small but definite lump in the right side of my neck.

Since I have a portable ultrasound, I looked at my thyroid nodule and found it to be about 1.8 cm, with some internal calcifications and a bright capsule. It was slightly darker than the surrounding thyroid tissue and had a few visible blood vessels.

I read about thyroid nodules and found that:

1. They are being noticed much more frequently because of increased use of CT scanning and ultrasound imaging.

2. They are very common. Nearly half of people will have significant, greater than 1 cm, thyroid nodules at autopsy.

3. About 5% of thyroid nodules are cancer, and cancer is more common in younger people, people with a family history of thyroid cancer, history of radiation to the head and neck, rapid growth of a nodule and larger nodules.

4. Experts generally recommend biopsy (taking a thin needle sample) of nodules over 1 cm in size.

5. Thyroid cancer is being overdiagnosed due to biopsies, because a needle can pick up a little bitty thyroid cancer which would never have been any problem over a person's life.

6. Some thyroid cancers will kill people. Most will not. It's hard to tell which will do what even after evaluating the tissue taken at a biopsy.

So I decided that if mine were a cancer which would cause trouble, it would almost certainly grow. I decided to follow it on ultrasound, measuring its size and watching what it looked like, and maybe get a biopsy if it grew.

It didn't seem to grow, at least not much. I was aware that it existed. I could feel it, though it didn't hurt. I was happy with my decision. Then I went to a talk about thyroid cancer at a major medical meeting. The speaker said that some thyroid cancers could grow very slowly over years and could still metastasize (spread to other areas.) Shucks. What if I got metastatic thyroid cancer? I could just imagine my family's displeasure. "It's a fool who has herself for a doctor." Also the expense, the plans forsaken. I decided to have it biopsied.

I went to a radiologist friend who said she had done many and assured me it would be painless. I scheduled it a week after my decision. I found that I needed a preoperative physical exam, which was a problem because I didn't have a doctor and hesitated to fill out my own paperwork because I figured I couldn't get away with it. So I had a physical exam which wasn't bad at all. I shuttled the paper copy to the radiology department. They still lost it, but eventually found it, and all was as it should be.

The radiology department is very familiar to me. I knew the smell and sound and paint color of the room in which I donned my hospital gown. The radiology technician gooped my neck with ultrasound gel and took about a million pictures of my nodule, measuring its length, width, height, observing its color doppler signal, looking for other nodules that might have hidden from my examining hand. My radiologist friend came in. We discussed things we agreed upon. We argued about the utility of mammography. That was probably not a good move, since she would then stick my neck with a variety of needles.

She numbed the left side of my neck with a lidocaine injection. I asked her if she knew that the nodule was on the opposite side and she reassured me that she hadn't been born yesterday and had performed this procedure before and knew exactly where my nodule was. She introduced a long needle from the wrong side of my neck into the nodule on the other side so as to avoid poking my carotid artery which was really quite close to my nodule. The bright shiny capsule turned out to be incredibly tough, requiring rather vigorous stabbing to get a sample. She then informed me that she recommended we do a core biopsy as well, since the pathologist appreciated a larger piece for evaluation. This was done through a type of coaxial cable. The core was taken with a gun which made a disconcerting thump as it removed tiny pieces of my thyroid. She showed me the little bottles with chunks of tissue it them. The hardware came out of my neck. Blood was mopped up.

It didn't hurt very much. Maybe a little like being strangled without the can't breathe part. Maybe not that bad, since I've never actually been strangled and wouldn't know. There isn't much numbing, just at the place where the needle goes into the skin because the thyroid itself has only dull pressure sensation. Swallowing is rather sore for a few days, however, because the thyroid moves up and down with every swallow.

Weeks later the bills began to arrive. I have medical insurance these days, through the hospital where I work. The total charges were $2,361. About half of this was for the ultrasound, about $300 was for the pathologist to read the slides. Another approximately $300 was to the radiologist, with free update on the utility of 3-D mammography and $500 was for supplies such as needles and coaxial cable. "Adjustments" due to using the hospital, which provides the insurance, for the whole procedure reduced the cost by a bit over $1000. So insurance paid $820 and I paid about $500.

The results came back "non-diagnostic." There was not enough thyroid tissue to be sure it's not cancer. Up to 20% of thyroid biopsies are non-diagnostic.

My initial reaction was that I was looking for cancer cells and they didn't find cancer cells and so I'm fine. It turns out that this is about right. There is a study from 2014 in which patients with non-diagnostic results on fine needle aspirate had a repeat biopsy (which I would not do because ouch, in so many ways). These patients almost never had cancer diagnosed, and almost all of those who did have abnormal repeat biopsies turned out to have false positive results. This means that they had a significant surgery removing a part of the thyroid and there was no cancer.

What I learned from my thyroid biopsy:

1. They are very expensive and the cost to even a well insured consumer is not small.
2. A thyroid biopsy is not painless. It is also not horribly painful. I do not want another one.


In the big picture, there is not a lot of value in routinely evaluating thyroid nodules with biopsy. There are 240 million adults in the US. About half of them probably have thyroid nodules greater than 1 cm. Performing an uncomplicated biopsy on all of them would cost about 240 billion dollars, assuming no repeat biopsies, diagnosing 6 million of them with cancer. Thyroidectomy and further treatment and followup of these diagnosed patients could easily cost that much again, adding up to nearly half of the US's yearly healthcare spending. A not insignificant number of people would suffer damage to their recurrent laryngeal nerve, limiting their ability to speak and sing, or lose the function of their parathyroid glands which regulate calcium balance. Of the cancers discovered, quite a few (hard to know the number) would never cause harm if untreated. Only about 1900 people die of thyroid cancer each year in the US and some of these are due to very aggressive cancers that will be fatal regardless of when or whether surgery is done. Despite an increase in detection and surgery for thyroid cancer in the last decade, there has been no change in death rates for this disease.

In the smaller picture, specifically the picture of an individual person with a lump in the thyroid, it is difficult to know what to do. Thyroid cancers can metastasize and kill a person. They just don't do that very often. Reassurance is valuable. Being diagnosed with cancer that would have caused no harm could be devastating. Being diagnosed early and avoiding death is priceless but extremely unlikely. As a doctor my practical approach should probably be to avoid searching for thyroid lumps in patients with no symptoms and to try to help those patients whose lumps come to light navigate the dangerous waters of further medical evaluation.


Thursday, June 2, 2016

Thinking beyond hospice

I recently attended the death of a friend at his home. He had a disease that was terminal and untreatable and he and his wife had finally decided on no further medical treatments that would require hospitalization. He was not very old and had been cared for by his children and wife during the previous 4 months that he couldn't care for himself. Time had become short and valuable and he had become weak, so he didn't amend his POST (Physician's Order for Scope of Treatment) to indicate that he wanted no resuscitation, though his wife and family knew his preferences. He had not entered hospice because his needs were adequately fulfilled by his family, friends, his physicians and home health.

When his wife noticed his breathing had changed, she called me, a friend of the family. I had offered to be available to come over for any medical situation in which they might need a rapid house call. I arrived about 15 minutes later and he had just died. I confirmed the situation with my medical gadgets. We were all sad and tearful and we talked and hugged and talked some more. I called the police, reported the death and the fact that it was expected. A kind and respectful sheriff's deputy came out and took a picture and a couple of statements. I called the local funeral home and a couple of guys who were on call came over with their stretcher and bag and quilt to collect him. About 90 minutes after I got the first call, his body was on its way to the funeral home and thence the earth and eventually the far corners of the universe. We sat and talked as the sun went down.

It was a good death, as much as a death of a vital and gifted person with plans can be good. It was a hospice-free home death, surrounded by family and friends. Such a thing is becoming vanishingly rare, and it made me think. Maybe we could make this easier. Maybe our community could reclaim the wisdom that it takes to facilitate better deaths, with or without hospice, nuanced to our needs and resources.

Hospice care is intended to be a holistic approach to providing support to dying patients during their last 6 months of life. The concept of hospice dates back to medieval times. Wikipedia says that in 1090 there is evidence that places existed which were devoted to care of the incurably ill, staffed by crusaders. There have been institutions for treatment of people who are dying since then, likely because of the clear need for dedicated care for people who are vulnerable and in pain and unable to advocate for themselves. Hospice at home was encouraged by Elizabeth Kubler-Ross (author of the book On Death and Dying), arguing that we shouldn't institutionalize people who are going through a universal life process. Legislation to pay for hospice care passed in the early 1980's in America. Hospice care has increased in popularity, more than doubling the number of patients utilizing the service and the amount of money spent in the last 10 years. This year an industry report predicts that the US will spend over $25 billion on hospice care. (It will also save several times this amount of money by providing appropriate care for the dying rather than futile procedures in a hospital setting.)

Hospice is extremely valuable in our culture which has lost the habit and skills of taking care of the dying at home. They provide a consulting nurse who keeps in touch with both the patient and his or her doctor, providing adjustment of medication to ease suffering and equipment such as hospital beds or shower chairs that may become necessary. They provide 24 hour phone advice and expertise regarding the dying process. They organize volunteers who will spell a caregiver to go out for a walk or shopping and aides who can help with bathing. Besides being valuable, hospice is also extremely expensive (mostly paid for by insurance including Medicare) and often feels like a one-size-fits-all solution. Hospice is difficult for introverts and people who treasure their privacy. "Going on hospice" can be demoralizing. Hospice is mostly not available to people who are still undergoing life-prolonging treatments such as chemotherapy. The use of pain and anxiety medication often seems heavy handed. I have ranted about some of these issues in the past. All this aside, I am truly grateful for the existence of hospice services and devoted hospice workers who make dying at home and in peace easier.

But I think we can do more and maybe better. My friend who died, and his family, needed his wise friends and his multidisciplinary team organized by his specialist, his flexible and understanding primary care physician and, in the end, me to smooth the difficulties of his passing. It turned out that he needed a bare minimum of medication and remained intelligent and interactive up until nearly his final breath. He didn't need hospice, but he did need help. I think there is support that a community can provide that is beyond what a hospice organization does.

What we need is a network of people in our community who are good for different things, to share with each other and with people somewhere on the dying spectrum what they know. Emergency medical technicians know what needs to be done when somebody dies at home of a terminal disease and so do I, but families of dying people should know too. It would be reassuring. Lawyers know about what is needed to have a valid will. Priests, nuns and other clergy people are skilled in helping people find meaning in the process of dying. There are people in my community who always seem to be there when someone is very sick and they are comfortable with some of the worldly aspects of the end of life. There are people who have special relationships with animals who could give comfort by visiting with a cuddly creature. There are musicians of all description and artists who can brighten a dreary space. People who have recently gone through the death of a loved one might be glad to sit down for a cup of coffee or come along for a doctor's appointment to take notes or ask the right questions. They may know how to make the funeral process less expensive. There are social workers who would be founts of good advice. Some people know about helping write a life history. Some people can do guided imagery or hypnosis for symptoms control. There are needs and solutions I haven't thought of, and somebody in my community knows about them.

When I was pregnant with my second child, we hired a doula. She was a woman who had lots of experience with birth and who helped me with questions I didn't want to ask an obstetrician. She encouraged me, shared stories and sat with me the entire time I was in labor, which was a long time. Because of her confidence I didn't feel frightened and I didn't need labor anesthesia. There are also doulas for the end of life. There are none in my community, but I think there are people with the basic wisdom and experience to be a companion for a patient and family during the dying process. Death can be frightening but it doesn't need to be.

This network of people would not displace traditional hospice, at least not in most cases. It would be a volunteer organization and, with the possible exception of doulas, there would be no requirement to be "on-call." This would create new connections within our community. There would be unexpected and probably positive consequences. Each person who volunteered would know that, although they are giving now, they will be receiving at some point because death is going to happen to all of us.

The hospice movement that gained steam in the 1980's was very important. It helped move death out of the hospital and the intensive care unit and back home, where we can be surrounded familiar things that bring us comfort. I think we are ready to take the next step. We may be ready to use our collective wisdom to find the meaning in life's end, beyond the mistaken concept that death is a failure of medical technology. Life is valuable in part because we know we will die. Like birth, we only get to do it once. Maybe we can be intentional about it and help each other out by sharing what we do well.

Thursday, May 26, 2016

Is there a pill to make you live longer? The HOPE-3 trial and the hype that will surely follow ...


Today in the New England Journal of Medicine (NEJM) an article has appeared reporting the results of the Heart Outcomes Prevention Evaluation-3 (HOPE-3)trial. Exciting simplifications are sure to follow in the news. If you would like to stop reading now, the answer to the question posed in the title is probably no.

The question:

For many years researchers have discussed the possibility of a creating a pill that might contain several kinds of medication that would reduce people's risk of dying of cardiovascular disease. It is an attractive thought. Since cardiovascular disease is the major cause of death globally, reducing that risk has the potential to vastly reduce death and disability. Originally we thought that a suitable "polypill" might contain something to lower the blood pressure, something to lower cholesterol and something to reduce the risk of blood clots. Many studies have looked at the mortality benefits of various blood pressure pills, cholesterol lowering strategies and anti-clotting drugs and we have found that some of them help some people to some extent and some cause some people problems. Drat. So complex.

The history:

The original HOPE trial looked at a blood pressure pill (ramipril) which was added to whatever other medication a group of people at high risk of cardiovascular disease were taking. It lowered the risk of heart attack, stroke and death significantly enough that the study was stopped early and drugs in the ramipril class (Ace inhibitors) were aggressively prescribed, especially for patients with diabetes, probably to good effect.

The HOPE-2 trial looked at using vitamins to reduce homocysteine levels, which appeared to be a significant risk factor for heart attack and stroke. The studied doses of vitamin B6, B12 and folate did not reduce any of the outcomes they looked at. HOPE-2 was dashed.

In 2007 HOPE-3 began, looking at a combination of blood pressure medication and cholesterol medication, specifically to reduce death from heart attack or stroke, new heart failure, cardiac arrest or non-fatal heart attack or angina. The study was performed in academic medical centers all over the world, including the US, Europe, China and India, South Africa and Southeast Asia. Over 14,000 patients were enrolled, limited to men 55 and over and women 65 and over with intermediate cardiovascular risk (calculated at about 1% per year). Women 60-65 years of age were eligible if they had one of several specific risk factors, including glucose intolerance, smoking and high waist to hip ratios. These were people who had never had heart problems or strokes.

Drug company involvement:

Astra Zeneca helped fund this study along with the Canadian Institutes of Health Research. The cholesterol and blood pressure medication used in the study was on patent and sold by Astra Zeneca. The cholesterol pill was rosuvastatin (Crestor) and the blood pressure medication was candesartan/hydrochlorothiazide (Atacand/HCT). There were many drugs to choose from in the categories of effective blood pressure reducers and statin cholesterol medication, some of which would have been cheap and generic. The drugs they did choose are now generic but not yet cheap. I suspect Astra Zeneca hoped the study would have ended in time for them to reap financial benefits as their particular drug proved miraculously effective, or that the combination of the drugs could be made into a new formulation that would extend their market share.

So what happened? Getting to the point.

First there was a run-in phase. The 14,000+ patients were given the study drugs and about 2000 of them dropped out because they didn't tolerate them or didn't want to participate anymore. 12,000 patients were left. Of these about 3000 took placebo pills, 3000 took the blood pressure pills only, 3000 took the cholesterol pill only and 3000 took both blood pressure and cholesterol medication. After about 5.5 years, the patients taking blood pressure medication did not have a significantly lower risk of death, heart attack or stroke or the other cardiovascular outcomes. The patients taking cholesterol medication did have a reduced risk of death and cardiovascular outcomes. Taking both blood pressure medication and cholesterol medication was no better than just taking the cholesterol medication.

How big was the effect and how much does this cost?

The article quotes a hazard ratio of 0.71 for patients taking the combination medication, meaning that the medicated patient has 7 tenths the risk of a bad outcome of the unmedicated patient. The raw numbers are way more interesting. After about five and a half years of taking the combination of drugs or placebo, 163 patients in the active drug group had died and 178 of the placebo group had died, a difference of 15. At the present cost of these drugs, about $280 per month, it would cost about $3.7 million per life saved, which is pretty steep. Just taking the cholesterol medication, which is really the only one that had a positive effect, would cost about $2.6 million per life saved. If there were drugs on a $4 a month plan that did the same thing  we might get down to a very reasonable cost of $53,000, assuming no other associated costs like doctor visits or lab testing (which is not a fair assumption.) Death is not the only thing we care about, of course, but other differences, such as numbers of hospitalizations, were not much more impressive when I reviewed the supplemental data.

How about side effects?

To begin with, 2,000 of 14,000 patients did not like or tolerate the study drugs, so some of them probably had intolerable side effects. During the study, however, there weren't many important side effects except a bit more dizziness in the patients on blood pressure medication, which apparently didn't do them much good anyway. There was some muscle pain, but patients on placebo also had that. The dose of the cholesterol pill was very low, which might have explained the pretty awesome side effect profile. Also the patients most bothered by side effects probably dropped out in the run-in period. By the end of the study only about 70% of patients were still taking the prescribed drugs, so there may have been intolerance that was not reported. There was no excess of development of diabetes, perhaps because of the very low statin dose. Good studies have shown more development of diabetes in statin users, but doses are often significantly higher.

Other interesting findings from the supplemental data:

I was very pleased that the NEJM published a well written summary of data that didn't get discussed in the article. There were some really weird things that showed up.

  1. South Asians and to some extent Chinese subjects did not have near as much benefit from the study drugs as did subjects of European descent. 
  2. Stroke risk was actually higher for patients with borderline high blood pressure when they were treated with the blood pressure lowering drugs, though reduced for patients with higher and lower blood pressures. 
  3. Patients with the highest cholesterol levels (LDL greater than 141, mean of 166) did not benefit from treatment with cholesterol lowering drugs. That's really strange and counterintuitive.

Bottom line?

We have not discovered a pill yet that will make everyone live longer. Taking a statin drug which lowers cholesterol (who knows if that's the important effect) may lower your risk of cardiovascular disease or death, but you need to take it a long time to make a small difference and we aren't sure which one is most effective. Most people who take statin drugs (Lipitor, Crestor/rosuvastatin etc.) for primary prevention (meaning they haven't had heart attacks or strokes) will not benefit from them. Low doses of Crestor/rosuvastatin usually have a low risk of side effects. Treating normal or slightly high blood pressure with low dose candesartan/HCTZ doesn't reduce the risk of heart attacks, strokes or cardiovascular death. Navigating the pros and cons of all of these pills and potions is neither obvious nor simple and is best done with a doctor who you know and trust.


Thursday, May 12, 2016

Medical error--the third leading cause of death, or not nearly so simple?

Splashed over news feeds this last week is a reference to an article published last week in the BMJ (formerly known as the British Medical Journal) that states that "medical error [is] the third leading cause of death in the United States."

What is this article actually about?

The new article refers to research done over the last 2 decades, and most recently an article by NASA toxicologist and patient safety advocate John T. James PhD in the Journal of Patient Safety in 2013. Dr. James evaluated 4 previous studies and estimated that 400,000 people, approximately, die yearly in the US of conditions that were either caused by or, more often, made worse by medical error.

That article, too, was met by outrage and was widely quoted and misinterpreted. I think hardly anybody actually read the article. Headlines read "Deaths by Medical Mistakes Claim the Lives of 400,000 People Each Year."

No new data, but a new way to think about it:

As far as I can tell from reading this most recent article, in BMJ, there is no new data. There is just the realization that if this many people are dying of medical error, it should be showing up somehow as a major cause of death, just like heart disease or cancer. The reason that it is not is because the questions that are asked on death certificates do not include anything about whether medical error had occurred. The article, quite correctly, states that this should be documented. Documenting this is the first step toward making major changes that will keep patients safer.

So what did the original article actually say?

When Dr. James' article came out in 2013, I read it and wrote a blog commenting on the study, its methods and what medical error looks like from my experience. Dr. James kindly responded in a comment,
"Thank you for putting my JPS study in an appropriate perspective. Some folks like to sensationalize the results as if these patients die only because of a medical error, and that is not what I wrote or intended."
The blog from 2013 was actually pretty good and completely relevant to the recent news release. You may want to read it. It does put the data into perspective.

Patient safety--very very important!

I am glad that this recent article has grabbed international attention for patient safety. What we read in USA Today and the rest of the popular press is not an accurate depiction of the problem, but the problem remains very real. Medical error is contributing to the deaths of hundreds of thousands of patients yearly. We, as physicians and healthcare providers, are trusted with the lives of vulnerable people, and it is up to us to build processes that allow our good intentions to be translated into good care.


Sunday, May 1, 2016

Practical and commonsense research from Ontario's Physician's Services Incorporated Foundation: Let them drink apple juice!

Today in JAMA online (the Journal of the American Medical Association) a delightfully practical article was published regarding how to help little children recover from gastroenteritis (stomach flu.) The authors, Doctors Stephen Freedman, Andrew Willan, Kathy Boutis and Suzanne Schuh, compared the health of over 600 children aged 6 months to 5 years, when given a medical rehydration solution to drink versus diluted apple juice along with the fluids that the child preferred. These children were not chronically ill or severely dehydrated, but were sick enough to have been brought by their parents to the emergency department and were at risk for needing hospitalization or intravenous fluids.

In previous studies oral rehydration with electrolyte solutions such as Pedialyte, which contain over twice as much sodium and 6 times as much potassium as sports drinks, along with much less sugar, had performed well in preventing hospitalization or return to the emergency department. Theoretically, children would need electrolytes to replace the ones lost in diarrhea or from vomiting, and extra sugar would just draw more fluid into the intestines, worsening the diarrhea. In the children studied in this recent research, however, giving a teaspoon of dilute apple juice every 2-5 minutes and treating vomiting with a very effective anti-nausea medication, ondansetron, by mouth, worked at least as well, actually significantly better than the same routine using bottled electrolyte solutions. This was particularly true in the children who were over 2 years old and so had definite taste preferences. Children given dilute apple juice and then liquids that they preferred were less likely to be admitted to the hospital or need intravenous hydration than children who were provided oral electrolyte solutions.

There has been a magic associated with giving children Pedialyte or similar solutions for their mild intestinal ills, despite the fact that it is more expensive (1 liter costs about $9, though may be as cheap as $5 when bought in bulk) and doesn't taste very good. Children mostly don't mind it, but some really do, which can be a big factor when they are feeling queasy. This study presents evidence to allow parents to give their children pretty much any liquid that sounds good, making an extra trip to the pharmacy with a sick child unnecessary.

Now oral electrolyte solutions and apple juice have both been available from many manufacturers for many years. What drug company, then, would be interested in funding this lovely research? None, of course. Could it have been funded by a governmental agency? Yes, I guess so, though much of that grant money is very hard to get. This study, though, was funded by a private foundation with a very interesting story.

In 1947 physicians in Ontario, Canada, joined together to create a pre-paid health plan. The physicians pro-rated their fees to stay within budget, and eventually 8000 doctors participated. In 1969, the Physician's Services Incorporated health plan ceased to exist and was replaced by a state run entity, now the Ontario Health Insurance Plan. There was still money in their account when they stopped providing services (they must have been doing something right) and the physicians decided to use it to create a foundation to improve the health of the citizens of Ontario. The original investment of those physicians was $16.7 million, and in the years since inception over $167 million has been paid out in grants. They now have around $90 million from which they fund over $3 million in grants yearly.

If you are interested, read the 2015 annual report for the foundation. The projects they fund are wonderful. There are little grants, one for $5500 to a physician who wanted to study lower doses of a testosterone product for female to male transsexuals. There are larger grants as well. There is a project to grow mats of human cartilage from small numbers of cells to heal the damage of osteoarthritis, reducing the need for joint replacements. There is a fellowship for a researcher who will take scientific research and bring it to the bedside, this year a nutritional expert who works on creating healthy diets. The money granted to this person is to free them up to do work that will not provide them any likely financial benefit. There is a study to look at the side effects and impacts of those side effects on patients who take the (often not very effective) drugs for Alzheimer's disease. There is a study looking at whether giving children who receive antibiotics in the hospital a probiotic milk product (kefir, I'm thinking) reduces their risk of getting antibiotic associated diarrhea. The studies are all like that: practical, meaningful, unlikely to increase healthcare costs and likely to improve health. They are studies that are not often done in the US, where drug companies are our major funding source, expecting to make more money selling drugs than they spend on research.

The PHI foundation is much smaller than the Rockefeller, Howard Hughes or Bill and Melinda Gates foundations which privately fund research in the US. Even so, they helped Dr. Freedman et al publish a paper that will allow the next generation of babies and toddlers to drink dilute apple juice rather than electrolyte solutions and be more likely to stay out of hospitals as they recover from their tummy troubles. Their other grants are just as good. They are a model of medical research funding I have not seen before. They are private individuals, doctors even, who have worked together to do something great. They are not super rich philanthropists, drug companies or federal government agencies.  This organization is making a powerful and positive impact by funding and encouraging researchers who are wise and curious.