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Sunday, April 27, 2014

E-Cigarettes and the FDA: Where should we stand?

People have smoked tobacco for centuries, possibly thousands of years, and cigarettes were first machine made in France in the 1880's. In the US, smoking peaked in the year 1965 when 50% of men and 33% of women smoked, with a per capita consumption of over 4000 cigarettes per year. When health effects of smoking began to be widely publicized, particularly its association with lung cancer, cigarette smoking began to decline.

Nicotine, the psychoactive ingredient in cigarettes, is addictive, producing a withdrawal syndrome that is at least partially relieved by nicotine replacement. Cigarette smoking, though, also has cultural meaning, which has contributed to its popularity. For decades therapeutic nicotine replacement has been available to people who want to quit smoking, first only by prescription, but now over the counter since the 1990's. The first product, a nicotine chewing gum, was released in the late 1970's, followed by a patch, a nasal spray and finally an inhaler. The inhaler delivered an aerosol of a nicotine solution from a cartridge attached to a small plastic mouthpiece which is absorbed primarily through the mucus membranes of the mouth. My patients told me that it tasted nasty and it made them look like they were sucking on a tampon. It was a great idea, but not very well executed.

It always seemed to me that what was really needed was a device that looked like a cigarette and delivered nicotine to smokers without the toxic chemicals that were associated with burning tobacco. Nicotine itself, other than being addictive, is not particularly toxic and certainly doesn't cause lung disease, atherosclerosis or cancer. In 2003 a Chinese pharmacist Hon Lik (per Wikipedia) invented the first electronic cigarette which vaporized a solution of propylene glycol and nicotine for inhalation. Within a year a similar device was marketed in China for helping people quit smoking. Other technology has subsequently been introduced, mainly based on the aerosolization of a nicotine solution by a battery powered heated coil inside a vaguely cigarette shaped device. Flavors are often added, and some e-cigarettes have only flavor and no nicotine. European tobacco companies have been enthusiastic about inventing and developing their versions of e-cigarettes, and Phillip Morris, a US tobacco company, has bought the rights to a nicotine delivery device based on the aerosolization of nicotine by pyruvate, which would not require a battery or produce smoke.

Looking online, I see that I can buy an e-cigarette starter kit for about $25, and the e-juice (nicotine solution) to fill it for about $1/ml, and it looks like 1 ml yields about 120 puffs. I can also buy a pack of FDA approved nicorette inhalers, 20 in a pack, for about $30, and according to the package a smoker would use 3-6 cartridges a day. Sounds like about $7.50 a day. The forums on e-cigarette use are all over the place, but it sounds like a heavy user might inhale 4 ml a day or so, a more moderate one 1 ml, so $1 to $4. Disposable ones can cost more. Cigarettes, depending on where you live, cost upwards of $5 a pack, as much as $14.50 in New York.

E-cigarettes have developed quite the following, and have their enthusiastic and stylish supporters. Using an e-cigarette, or cartomizer, is called "vaping" and some people are excited not just about the nicotine, but also about the devices and flavors and overall coolness of the technology. Poisoning has been reported, primarily due to young children drinking the replacement solution. There is no significant evidence of toxicity related to using the devices as recommended. The Food and Drug Administration (FDA) does not presently regulate e-cigarettes, but recently announced a plan to categorize them as a tobacco product, requiring producers to register and to share with the FDA details about how they are made and what they contain. They also would not allow free samples or purchase by anyone under the age of 18. Manufacturers would not be able to say, without proof, that e-cigarettes are safer than cigarettes and would have to say that nicotine is addictive. These proposals are still being discussed it is not clear when or if they will be adopted.

Which brings up a very important point: We don't actually know if e-cigarettes are safe or if they help people quit smoking. It seems likely that if there is a cheaper alternative to cigarettes that gives a person the same nicotine high, tastes like pomegranate (or strawberry or whatever) rather than burning leaves, can be used in public places and costs a fraction of what cigarettes do, people will tend to prefer it. But we don't know this. It seems likely that a product that contains nicotine rather than burning leaves with associated carbon monoxide and carcinogens will cause less health problems, but we also don't know this. There are so many competing e-cigarette producers that none is likely to come up with the money to support research that would be convincing of the safety and effectiveness of the whole class of products, including those made by their competitors. Some small studies are mostly encouraging. Compared to cigarette smoke extracts, the extracts of e-cigarettes are much less toxic to mouse fibroblast cells. Air quality was not significantly affected by e-cigarette use for the compounds tested, including glycols (which would be expected to be found in e-cigarette smoke) along with other standard pollutants found in high levels when cigarette smoking is present. About 400 e-cigarette users were followed for a year, to look at use of both e-cigarettes and tobacco cigarettes. E-cigarette use was about stable over the year, and for former smokers there was a 6% relapse rate to tobacco, whereas about 46% of subjects who smoked tobacco as well as e-cigarettes completely ceased using tobacco at the end of a year. One study of smokers and nonsmokers showed no significant reduction in lung function acutely after using e-cigarettes briefly, but another slightly larger study of smokers only showed a restriction of airflow in smokers after using e-cigarettes for 5 minutes. No studies have addressed long term lung effects of regular use of e-cigarettes, and this information is much more relevant.

So where should we, as physicians, stand on the subject of e-cigarettes? First and foremost, not on the side of ignorance. I hear many physicians speak out for or against e-cigarettes without knowing anything about them. My own hospital banned them, as have many other hospitals, based on not very much real information. Countries around the world ban them or regulate them or ignore them completely, based primarily on opinion. They are legal in Germany. They are regulated as a medicinal product in Denmark. They are illegal with a heavy fine in Hong Kong, but legal in China. In Hungary it is legal to buy them and use them but it is illegal to sell the nicotine solution.

I tend to think that e-cigarettes are a good invention. I suspect that if they came out several decades ago our smoking related morbidity would be much lower. They have the potential to come pretty close to eliminating tobacco smoking, much more effectively than regulation and physician nagging has done. They will not not reduce nicotine addiction and have the potential to increase it, but it is not clear that nicotine addiction is a public health problem. Clearly good research is important, and it is likely that convincing evidence of safety will not be available for years, and will have difficulty finding funding. Phillip Morris probably will be first to show their product to be safe, if it is, but it will be in their best interest to make sure that data is not generalizable to other e-cigarettes.

The FDA is right to regulate the e-cigarette industry and to require that the manufacturers be honest about what is in them, since there are quite a number of chemicals that make people sick when they are aerosolized and inhaled. Even if e-cigarettes aren't exactly food or drug or tobacco product, they are somewhere in between all of these things and their popularity gives them tremendous potential to do harm if nobody is watching. Even so, creating excessive burdens that interfere with their ability to successfully undermine the tobacco industry (about which there is truly nothing good to say) would be an error.

Wednesday, April 16, 2014

Pocket Ultrasound Machines: "Why doesn't everyone have one of these?"

For about 2 years now a tiny ultrasound machine has been part of my standard physical exam tools as I take care of patients in the hospital and in the outpatient clinic. In November of 2011 I first picked up an ultrasound transducer in a continuing medical education course on bedside ultrasound for emergency physicians. I am an internist, not an emergency physician, but I was interested in bedside ultrasound and it was the emergency physicians who were giving the most interesting course. It was transforming for me. I was able to see internal anatomy and physiology and eventually, with lots of practice, I was able to make diagnoses more quickly and accurately. I bought a pocket ultrasound machine so I could make bedside ultrasound a seamless part of my practice

It was an unexpected and welcome bonus that my patients and their families loved it. I would share the moving ultrasound pictures with them, often having them hold the machine so I could point out how beautiful their internal organs were and what we could see that helped give us a clue about their disease process. Many of these same patients also got full, detailed ultrasounds or other imaging by radiology technicians, but since the technicians aren't supposed to discuss findings with the patients and often they couldn't see the screen, it wasn't nearly as gratifying.

The most common comment I get from patients is, "Wow, that's really cool!"  "I agree!" I answer. Then they will ask, "Why doesn't everyone have one of these things?"

That is kind of a difficult question. "They're pretty expensive," I usually say. They are. At least for now. The little machines (Vscan, by GE) retail for over $8000, though you can buy them cheaper used or overseas. Physicians balk at spending this amount of money on a piece of equipment. Most of the expensive gadgets we use are owned by hospitals or by our group practices. Musicians, however, who make a fraction of what we do, buy their own musical instruments which often cost in excess of $10,000. I'm not sure the cost ought to be a serious consideration. Other doctors often ask me if I bill for my exams. I don't, because billing and the detailed documentation and posturing that would be necessary to prove to an insurance company that an ultrasound was necessary would take more time than I have. I report the results in my narrative of the physical exam, much as I do the findings of my ears or my hands or eyes. There are billing codes for limited ultrasounds, and if I were able to record and store my images easily I could probably boost my revenue, but that would make me feel just a little bit conflicted every time I did it. I would have to tell the patient that I was charging for it which would probably make them feel conflicted as well, or maybe choose to forgo the exam, which would mean that I would know less about what was going on and would be more likely to make a mistake.

"It also takes a long time to learn," I add. I have spent hundreds of hours in  learning from good teachers, mostly in person, but also online. I have done many thousands of exams and have reviewed a fair number with experts. But it is actually pretty quick to get good enough to be sure of a handful of different things that make a huge difference in making clinical decisions. After that, much like most of the things we do in medicine, learning expands exponentially with on-the-job experience. Many students in medical school now are learning how to use ultrasound at the bedside as part of their standard training, which is really the best way to do it.

"When did those things come out? I've never seen anything like it!" say my patients. The little pocket model I have has been available for at least 5 years, and there have been portable ultrasounds for considerably longer. The company that makes mine has not been aggressive in marketing it, even though it is potentially as huge a deal as the introduction of the stethoscope, and other ultrasound companies have been incredibly slow in developing competitive models. Maybe it's just difficult to develop the technology, but I think it's a little less wholesome than that. Ultrasound is a huge part of what radiology departments in hospitals and clinics do. It has grown as we have become aware of the dangers patients are incurring with the expanding use of imaging based on x-rays, such as CT scans. Full scale ultrasound exams are performed by radiology technicians using machines costing hundreds of thousands of dollars, are read by radiologists or cardiologists and billed out for thousands of dollars each. If physicians at the bedside are doing these exams for free, or even for cheap, this has the potential to negatively impact huge revenue centers. It is not in the financial interests of the whole industry for the manufacturers to produce an awesome pocket machine. A bedside ultrasound, which takes minutes, is hardly the same as a full scale ultrasound or echocardiogram which can take almost an hour to perform by a technician who does only this. In some cases we may order more ultrasounds because of what we see, or think we see, at the bedside, but for some questions our brief and focused exam will be enough and will supplant imaging by the radiology department.

There is also abundant controversy about adding routine ultrasound to the way we practice medicine. It is a "disruptive technology" which means that it potentially changes things in far reaching ways, many of which can't be adequately predicted. We may see things inside patients that are best left unseen or are difficult to interpret. We may thus end up chasing findings that are nothing and costing patients more money and anxiety than we should. I have not found this to be true, however. Imaging of all kinds, especially the detailed kind that comes out of radiology departments, is often misleading and anxiety provoking. Think about the majority of mammogram abnormalities that turn out to be nothing or adrenal "incidentalomas," the small meaningless lumps we see on the adrenal glands when CT scanning the abdomen. Combining bedside imaging with examining the patient, talking to them and reviewing laboratory data has been much less likely to lead me to misdiagnoses than to appropriate ones.

Many older physicians are trying to adjust to changes that make them feel that they are losing the profession that they used to practice skillfully in the past. We are asked to learn to use computer systems to document patient visits, review medical histories and order treatments. We start to become data entry technicians, and we aren't very good at it. We are asked to learn continually changing algorithms for treating a myriad of diseases. We are required to provide excellent preventive medicine for our patients so they don't have heart attacks or strokes or get cancer, when research on the proper way to do this makes what was wise one day stupid the next. On top of this people like me with our tiny little ultrasound machines come along and say "Hey...there's this other thing you should do too..." But I would love for my overworked and stressed out colleagues to know that this is different. Data entry is not inherently fun. Robots or trained monkeys could probably stay on top of the preventive to-do list better than we do, and algorithms don't give us much job satisfaction, even if they do help us deliver evidence based treatments. Bedside ultrasound, though, is terrifically fun and despite the time and effort required, brings back some of the joy of being a real doctor. I say this after a quarter of a century of practicing internal medicine. I am an "older physician."

So, "Yes," I tell my patients. "I agree. It is incredibly cool. We are looking at the inside of your body together and learning things. It's unusual now, but I'm pretty sure it's not going to be too long before it's part of what most of us do."

Sunday, April 13, 2014

America's New Guidelines for Cholesterol Lowering Drugs: What do European Doctors Say?

In November of last year the American Heart Association released new recommendations on who should be taking "statins" (drugs like lipitor/atorvastatin), the most common medicines we use to control cholesterol levels. High cholesterol levels are associated with higher risk of heart attacks and strokes, and taking statins, which lower cholesterol, can reduce those risks. The drugs have pretty significant side effects, though, and not everyone with high cholesterol or other cardiac risks will actually have a heart attack or stroke, so it seems clear to most of us that not everyone should take statins.

The American Heart Association's 2013 guidelines
The new recommendations departed from prior ones in saying that we should prescribe statin drugs to patients with higher risk of heart attacks rather than just patients with high cholesterol. I wrote about the new recommendations here. It actually kind of makes sense, since even patients with relatively normal cholesterol levels may have lower risk of heart attacks when they take statins, and patients who have high cholesterol but no other risk factors may be vanishingly unlikely to have a heart attack regardless of whether they take the drugs. So, theoretically, the new recommendations would allow some people who have been taking statins entirely because of high cholesterol levels to stop taking them, which would be nice.

More statins: good idea or bad idea?
There has been considerable debate since these recommendations were released since they actually significantly increase the number of people who doctors may encourage to take statins. The data on whether giving statins to patients who have never had heart attacks will reduce their risk of heart attack or stroke is pretty weak, and it appears that statin therapy in this group of people does not reduce the risk of death or other disability. (Check out the audio discussion by Dr. John Abramson of Harvard University at The British Medical Journal online since the printed version costs money to read.) Statins appear to be significantly more effective in preventing heart attacks in patients who have already had coronary artery disease, including heart attacks or angina ("secondary prevention"). Almost all of the data we have on how effective statins might be has been financed, at least in part, by the manufacturers of the drugs, whose primary responsibility is to make money for their shareholders by selling statins, not to make patients live longer and healthier lives. The new recommendations would result in many patients without medical illnesses being starting on medications, what we call "primary prevention." Patients who are calculated (using a risk calculator) to have a 10 year risk of heart attack or stroke that is greater than 7.5% would be encouraged to take statin drugs.

How many Dutch people would be on statins?
A group of physicians from the department of epidemiology at Erasmus University in Rotterdam, the Netherlands, did a very clever study to look at what effect implementing these new recommendations might have had on a group of random Dutch people (average age 65 or so) they have been following since 1997. Using the data they had collected they found that 100% of the men and 65% of the women would have been recommended to take statins based on risk level. On average the men were calculated to have a 21.5% 10 year risk of heart attack or stroke based on the calculator and the women 11.6%. They were able to actually look at who had these events, and it turned out, at least for this population, the calculator seriously overestimated the risks. Only 12.7% of the men and 7.9% of the women actually had a heart attack or stroke. (Perhaps Dutch people have lower risk of heart attacks because they ride bicycles more. Physical activity is not entered into the risk calculator.) The authors conclude that using the risk calculator to determine whether to prescribe statins is inaccurate in their population and basically unnecessary over the age of 65 since nearly everyone would receive qualifying scores. They ask if the present guidelines are really advocating a blanket prescription for statins based on age.

Putting it all together
Statins may or may not make us live longer. If they do, it is a pretty small effect unless we have had prior heart attacks or coronary artery disease. They do have side effects. About 1 in 5 people who take them develop some problem, often just muscle pains and weakness but sometimes diabetes and probably thinking and memory problems. The new recommendations released in 2013 by the American Heart Association would have us encourage the majority of people over the age of 65 to take these drugs, as well as quite a few healthy younger people. Since drug companies are major players in funding research on statins, we may never get truly unbiased information about their risks and benefits. Healthy diet, regular exercise and not smoking are far more powerful ways to reduce risk of heart attack and overall death and disability due to all causes, but advertising this makes nobody any money. It is possible that guidelines which increase the use of statins will also make us just a little weaker, achier, stupid and diabetic.

Wednesday, April 2, 2014

Mammograms are not as awesome as we said they were: Damage control articles published in JAMA

A few weeks ago I wrote a blog which addressed a newly released study of the effectiveness of mammograms. This article, in the the British Medical Journal, looked at women who were followed over a 25 year period as part of a Canadian study, found that there was no evidence that mammograms reduced deaths from breast cancer. Most women who will die of breast cancer do so regardless of whether that cancer was diagnosed by a mammogram, and the few who are saved because their cancers were diagnosed earlier than they would have been if only clinical exam were used may have been canceled out by the far more significant number of women who were harmed by overdiagnosis, that is being diagnosed with a breast cancer that would never have troubled them had they not had mammogram screening.

I was concerned that this didn't set off a huge discussion among doctors and all of the rest of us about whether we should really continue to do regular screening mammograms. Our lives, health and billions of dollars rest partially on the answer to this question. The fact that it is so important is probably why the conversation has been so slow to start. Not doing the tremendous number of screening mammograms we now do would be very destabilizing since hospitals and surgeons and radiologists depend heavily on this revenue stream. Women's health centers at hospitals are primarily about mammograms and breast cancer diagnosis and treatment. These employ nurses and administrative assistants and social workers and counselors. There are ongoing and yearly campaigns designed to get women to get mammograms. A major change in policy has the potential to free up a great deal of financial and human resources, but at the same time jobs will be lost and budgets broken. If we accept that mammograms have lead to substantial overdiagnosis, this will have a huge emotional impact on women who have been diagnosed with breast cancer as a result of mammogram screening.

So it is not surprising that the response to this Canadian study was measured.

Today two articles were published in the Journal of the American Medical Association one addressing mammograms in general and the other mammograms in women over the age of 74. These articles have been published less than two months after the BMJ article and are already getting lots of press and lots of discussion. The article about the overall risks and benefits of mammography is a review of multiple studies, including the BMJ article, and is really interesting to read. It delicately steps around some strong evidence that mammograms have no particular value in saving womens' lives and comes up with numbers that nevertheless make preventative mammogram screening look unattractive. The conclusions are that mammograms do reduce breast cancer deaths, but on the order of 1-50 per 10,000 women screened for 10 years, depending on age. A total of around 300 will be diagnosed with breast cancer and up to a third of these cancers will be overdiagnosed, resulting in women presumably being treated with radiation, surgery and chemotherapy for tumors that would not have caused harm. Six-thousand of the 10,000 screened with mammography, fully 60%, will be called back during this 10 years for abnormal mammograms that will need further workup, including more imaging and biopsies. Still, the conclusion is that mammograms reduce breast cancer mortality, but only a little bit.

But what about the Canadian study published in February? This looked at women aged 40-59 who were screened with either clinical examination (examination of the breast by a trained health care provider) or mammograms plus clinical examination over the 5 year study period and then followed for 25 years. The only difference in the groups at 25 years is that the mammogram group had more breast cancer. There was no mortality difference. Did the Canadian women in the BMJ study play catch-up and get mammograms after the study was done and so reap all of the mortality benefit? If so, they appear to have also avoided a certain amount of overdiagnosis by taking their 5 year holiday. There are many ways to study the efficacy of mammogram screening, and none of the many studies that have been analyzed and meta-analyzed was really able to do a gold standard approach. Because of the fact that we have embraced mammogram screening as our standard of care, we have not done the definitive study.  Ideally we would compare a group of women who were denied access to mammograms for 25 years and only received clinical breast exams or breast self examination to a group who had mammograms at varying frequencies, say every 1-4 years, along with their clinical breast exams. No such experiment has been done so we rely on evidence gleaned from huge populations over many years but with less than ideal designs.

The other article in today's JAMA tackles the question of mammogram screening in patients older than 74. No actual studies have been done on this population and many countries stop recommending mammography for patients aged 70-75 years of age. In the US a significant proportion of women getting mammograms are over 74. Today's article concludes, based on extrapolating the data we have based on younger patients' data, that there would be a mortality benefit of mammogram screening if the women in question were expected to live 10 or more years. That is such a can of worms. I have very warm and respectful relationships with many older women who are my patients and I find it very difficult to admit to myself, much less them, that I expect they will die before 10 years elapse. That also assumes that I have any reasonable idea. The most important predictor of being alive tomorrow is being alive today, which is the message I like patients to take with them.

In a delightful juxtaposition, Dr. Mary Tinetti, an academic geriatrician, wrote an article about how extrapolating benefits of interventions from younger to older patients is often inaccurate. She doesn't address the mammogram issue, but her article is well placed. We really don't know what good or harm mammogram screening will do for our patients beyond the ages we have studied. It does appear, however, that overdiagnosis increases with age (see the BMJ article), so more women in their final decades will be diagnosed with breast cancers that would never have caused them harm if we continue to subject them to screening mammograms. I have watched my elderly patients suffer through radiation and chemotherapy and it is a lousy way to enjoy retirement.

So this kerfluffle about whether to do mammograms or not is a really big deal, and there is much damage control going on. It is interesting to look at this from the sidelines, and I am sure there is much that I am not perceiving. Many well meaning people are highly invested in the prevention of breast cancer and much good work is being done. Mammography is definitely not going away. It is a reasonable way to detect breast cancer, and detecting breast cancer comes before treating it, and we have improved tremendously in our ability to effectively treat and cure it. Mammogram screening for patients at high risk yields a whole different set of numbers than what I have quoted. There may also be ways to augment mammogram screening with other testing to make sure that the breast cancers we treat actually need to be treated. It is past time, though, that we question the wisdom of pushing for regular mammograms in unselected women over the age of 50.