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Tuesday, August 30, 2011

Is Lipitor good for you?--putting statins on the hot seat

In 1971, as medical science was wrestling with the observation that elevation of cholesterol levels was associated with heart attacks, a Japanese chemist named Akira Endo discovered a substance that inhibited the enzyme HMG CoA reductase and thus lowered cholesterol levels. His original chemical was never introduced due to significant muscle toxicity and the fact that it caused tumors, but not long after, a less toxic version was introduced under the brand name Mevacor (Lovastatin.) This drug was significantly more powerful in lowering cholesterol levels than the unpleasant and relatively ineffective drugs that came before. These are still used today, but are difficult to take, including ones that taste like sand and absorb cholesterol from the gut as well as high dose niacin which causes itching, flushing, worsens diabetes and exacerbates gout.  Lovastatin could be dosed once daily, was an innocuous capsule, and lowered cholesterol strikingly.

Since that time, many more HMG CoA reductase inhibitors (statins) have been released, and they all work pretty well. That is, they all work pretty well to lower cholesterol. It is true that high cholesterol is strongly associated with vascular disease, especially heart attacks and strokes, and that use of these drugs does reduce the risk of these things. Unfortunately, it is not entirely clear that these drugs make most people healthier or make them live longer.

Many good controlled trials have shown that statins, pretty much all of the statins, and there are quite a few, reduce the risk of vascular disease AND DEATH in people who have had heart attacks or vascular procedures to prevent heart attacks. But if statins were only used in those already affected, sales would not have topped $12 billion for lipitor (atorvastatin.) A recent meta-analysis evaluating all good studies of all statins did show that normal people with elevated cholesterol who were treated with statins did not live longer than those who were not treated.

There have been many many studies that have addressed the effectiveness of statins, partly due to the fact that there is so much money going into paying for these drugs, some of which can be routed back into science. The studies address risk of all kinds of diseases, vascular and otherwise, in all kinds of people, especially sicker subpopulations. It appears, for instance, that the very old who have had heart attacks do live longer if given statins. Diabetics, at least some diabetics, have less heart attacks and strokes, and live longer when given statins regardless of their cholesterol numbers.

Statins are very powerful drugs. They work to keep the liver from making cholesterol, but they also have some pretty diverse other effects, including stabilizing blood vessels and reducing inflammation that can cause heart attacks.  They also are somewhat toxic to mitochondria, the tiny cells within cells that are responsible for   the health of a myriad of different tissues in our bodies.  Because they sometimes injure mitochondria, they can cause muscle pain, and in some cases dangerous breakdown of muscle tissue.  The muscle pain is associated with damage that can be seen on muscle biopsy, which is usually, but not always, reversible when the drug is stopped. Other tissues that can be affected include liver, kidneys, gut and brain, and a small percentage of patients who take these drugs have symptoms that arise from these effects.  Muscle pain, however, is not rare, and in my practice requires stopping the statin drug in about 1/4 of patients who would like to be able to take these medications. Symptoms associated with statins can be really subtle and many patients who experience them assume that they are just getting old. Physicians are not very sensitive to the possibility of side effects with these drugs, partly because they are such an easy way to get cholesterol down.

If an evil alien race wanted to take over the world, statin drugs might be just the ticket. They would make those who are already damaged by heart disease live longer, and cause some portion of the rest of those taking them to become weak, flatulent and stupid. A drug that was indicated for a condition such as high cholesterol, that affects nearly 1/4 of people in developed countries and offers to reduce their risk of heart attacks and strokes would be so very tempting that most of us would take it. Clever aliens.

There is near consensus among academic physicians that statins are good for us, and that complaints about side effects are overblown and irrelevant. I am having trouble trying to find support for this in the literature, and real trouble ignoring the side effects that I see in my office. It is hard to ignore the power to sway us that may be wielded by a drug company that makes 9 billion dollars in a year on one of these drugs, as Pfizer does on Lipitor.

A couple of other matters deserve note. There are quite a few statins, from the less potent pravastatin, lovastatin and fluvastatin, up through the most powerful, simvastatin, atorvastatin, rosuvastatin and pitavastatin. Several are generic, and of these, the most popular is simvastatin due to its low cost and high potency. All of the statins can cause adverse reactions, but some are worse than others. Simvastatin is probably the most likely of all of them to cause muscle pain and to interact with other drugs in ways that increase those side effects. Drugs that interact with some or all statins include various antibiotics, warfarin, antifungal and AIDS drugs and as little as a cup of grapefruit juice. Higher doses lower the cholesterol more and increase adverse effects more, and only occasionally are shown to be more effective at reducing vascular disease. The most dramatic adverse effect of statins is a severe breakdown of muscles, called rhabdomyolysis, and that is more common in the elderly, those with underlying organ dysfunction and those who take medications to lower the triglyceride levels (fibrates.)

A recent article came out in the European Heart Journal, looking at long term followup of treatment with atorvastatin in a study of various medications for high blood pressure with or without cholesterol lowering drugs. The results were nearly impossible to understand, showing that people who were initially placed on atorvastatin who had high blood pressure did live longer, but primarily due to the fact that they were less likely to get pneumonia. Huh? In addition to that, after the two or so years that the study continued ( it was stopped early because the patients on atorvastatin had so many fewer heart attacks and strokes) nearly all of the patients in either treatment or control group were put on statins, so they were pretty much identical in all ways except for the first two years. As I read this, it would suggest that taking lipitor for 2 years, 11 years ago reduces your risk for pneumonia in subsequent years, which just doesn't make a reasonable amount of sense.

Bottom line: Lipitor is probably good for you if you have had angina or a heart attack and don't want it to happen again. It can cause a myriad of side effects, some of which can be pretty subtle but can significantly impact a person's life. If your cholesterol is just high, but your heart and vessels are fine, Lipitor (or other statins) might be very good for you, and might be bad for you, and it is kind of hard to know from the studies whether to take it. It is unlikely that Lipitor was invented by evil aliens, but if it was, they are really raking in the bucks.

Sunday, August 28, 2011

Preventing Alzheimer's disease and sudden death--can it be this easy?...and other stories of disease prevention

Reading through the Internal Medicine News today was surprisingly uplifting. This is a large format free journal that highlights studies presented in journals or in meetings around the world.  This time the most interesting articles were about prevention of disease.

Deborah Barnes and her associates calculated, using recent reviews on the subject, that improvement in various health and lifestyle conditions could potentially avert millions of cases of Alzheimer's disease.  These conditions, in order of importance, are physical inactivity, depression, smoking, hypertension, obesity, low educational attainment and diabetes. She calculates that half of the more than 36 million cases worldwide are at least partially due to these risk factors. This information is especially nice since all of these conditions are independently important and strongly impact a person's health and happiness in other ways.

Sudden death is usually due to a heart attack, though pulmonary embolus, ruptured aneurysms and major strokes are also culprits. It turns out that women who maintain a healthy weight, don't smoke, exercise regularly and eat a healthy diet have a 92% lower risk of sudden cardiac death than those who do none of these things. That's big! and if one combines this with the news about Alzheimer's disease, it sounds like good health habits might be a really good idea!

In addition to not dying of a heart attack and not getting Alzheimer's disease, it would be really nice not to get HIV. HIV and AIDS are now treatable as a chronic disease, and some of the misery suffered by those who are infected with it can be averted by regularly taking medications to kill the virus. Nevertheless, HIV infection is not fun. Safe sex, that is protection against contact with the body fluids of someone who is infected with HIV by either abstaining from contact or using condoms or other protective equipment is effective in preventing transmission. But safe sex is not always practical, as in the case of marriages or partnerships where only one member has the infection. It turns out that taking a regular daily dose of a combination HIV antiviral medication can reduce the incidence of infection of the non-infected partner by over 70% according to a study done in Kenya. The most effective preventive drug, Truvada, is not cheap and does have some significant side effects, which may limit the overall impact of this finding.

Thursday, August 25, 2011

Preventing health catastrophes--what works?

Today in the Journal of the American Medical Association David Jenkins MD and colleagues from Toronto, Ontario reported that certain dietary interventions really do help reduce cholesterol levels. Most patients believe, because we have told them, that improving their diets by eating less fat will significantly lower their cholesterol levels. According to a really well done study published in 1998, that is not true. Combining such a diet with exercise is helpful in reducing cholesterol, and probably also reduces many other bad health outcomes, such as diabetes, obesity and death. In Dr. Jenkins' study, however, patients were not told just to eat less fat, they were also instructed in what foods to add to their diets to reduce cholesterol. The study participants were instructed to eat a vegetarian diet and to add plant sterol containing margarine, soluble fiber (such as psyllium, oats or barley), soy protein products such as tofu and soy milk and peanuts or tree nuts. Simply being nagged to eat this way (2 sessions, total of 1 3/4 hours) lowered the cholesterol over 20 points (13%). The low fat diet, which was the control group, made almost no difference. Patients who actually followed the study diet had the best results, which is at it should be.

But having high cholesterol is hardly a health catastrophe. Heart attacks are catastrophes, and every year over a quarter of a million people die of heart attacks. We know that elevated cholesterol levels are a risk factor for heart attacks, but there has been no study that I can find that proves that lowering cholesterol levels by diet reduces heart attack. Perhaps it doesn't hurt, but even that is unclear. Cholesterol lowering drugs, such as the pharmacological blockbuster lipitor, definitely do lower cholesterol and lower risk of dying of a heart attack, but that may be due to any of a number of mechanisms, including lowering inflammation.

One of the most devastating catastrophes of aging is a bone fracture. As people age, bones become weaker and with relatively minimal trauma, such as with a low impact fall, can break. The most significant of these fractures is of the hip. Most hip fractures are fatal if untreated, and surgery to stabilize them is not a small thing. In the year following a hip fracture 15-20% of patients die, and many more require long nursing home stays.

People with osteoporosis are most likely to sustain hip fractures, and osteoporosis is increasingly common as our population ages. It is common to get a bone density study done after menopause to identify osteoporosis and physicians are often asked to prescribe medicine to strengthen bones when the bone density study shows that the risk of fracture is increased. Medicines such as fosamax (alendronate, now generic) can increase the bone density and reduce the risk of fractures, but all medicines for osteoporosis have side effects,  from esophageal ulcers to unintended bone fractures and jaw bone death. The side effects are infrequent, but that is no consolation to the occasional patient who gets the side effect. Because the medicines for osteoporosis are hard to love, we physicians often recommend to patients with waning bone density that they start calcium and vitamin D supplementation. These are inexpensive and pretty much natural, but there is no evidence that I can find that they actually work to prevent fractures. A 1998 study in the New England Journal showed that supplementation with calcium 1000-1500 mg  and vitamin D 400 IU daily slightly increased bone density, but did not reduce hip fractures. On the strength of that study, we physicians temporarily stopped recommending calcium and vitamin D, but we are back at it again, based only on some vaguely applicable studies of vitamin D alone in nursing home populations.

Of course, getting scientific proof of what works and what doesn't is closely attached to both funding and practicality. Drug trials can be performed in a double blind, placebo controlled manner, the most scientifically trustworthy design, whereas lifestyle and diet changes cannot be tested that way at all. It is very expensive to carry out a well designed trial of any sort, but big pharma has that kind of money, and can afford to spend it on science since the return on a positive study is very significant (Lipitor (atorvastatin) earned Pfizer 9 billion dollars in 2009).

What is a person to do? Should we as physicians stop giving health advice that is of dubious accuracy? Since people sometimes actually do listen to us and do what we recommend, should we work harder to produce some kind of guidelines for good health behaviors that will be easy to understand and of minimal complexity?

Friday, August 19, 2011

Fecal transplants: rethinking therapy for tummy troubles

Since Alexander Fleming first discovered penicillin in 1928 and the first sulfonamide antibiotic was introduced in 1932, medical science has created countless chemicals that inhibit the growth of disease causing microbes. Dirty wounds that would have resulted in certain death prior to antibiotic therapy were treatable and curable. It must have been a very exciting time to be a doctor.

In my lifetime, the number of antibiotics available to use to treat infections has grown to the extent that, even with constant vigilance, I can't keep track of them all. Antibiotics are more often prescribed not for life threatening infections, but for treatment of symptoms such as sore throats, stuffy noses and inflamed bug bites for which those antibiotics are undoubtedly not effective, symptoms which if left untreated would resolve on their own. These prescribed antibiotics kill bacteria anywhere in the human body where the blood delivers them, hitting complex bacterial communities much as a bombing raid might hit our home towns. Appreciation for the beneficial roles of these communities, or microbiomes, is increasing in scientific and medical circles, but indiscriminate use of powerful antibiotics continues to be common practice.

Of the many problems associated with use of antibiotics, resistant bacteria is one of the most commonly recognized. In the hospital setting a common scenario is development of severe diarrhea following antibiotic use, often leading to prolonged hospital stays, nutritional compromise and sometimes death. The usual cause of this diarrhea is the bacterium Clostridium Difficile. At worst, this bacteria, which is resistant to many common antibiotics and common in the human gut, will cause diarrhea, nausea and vomiting, abdominal pain, fever and a raw intestinal lining that can even perforate, releasing stool into the sterile abdominal cavity. There are two antibiotics that can attack Clostridium Difficile, but even at their most effective they can still leave viable bacteria which can multiply again, causing recurrent or chronic infection.

For more than half a century physicians have recognized that, since C. Diff occurs after the healthy bacterial population in the gut is devastated by antibiotics, that restoration of the good bacteria might lead to a cure. In 1958 a physician reported using an enema of stool from a healthy donor to cure this disease. More recently we have attempted to treat persistent cases with "probiotics"--supplements consisting of bacteria like those in yogurt, and another, similar to one used in making fermented spirits, Saccharomyces Boulardii. These tricks have sometimes worked, though not, by any means, infallibly. It is tempting to try to treat a disease like C. Diff with a bacteria that smells good and is encased in a gel cap, one which is well defined and undeniably safe. Nevertheless, it makes much more sense that a persistent and pernicious pathogen would be vanquished by an army of cooperating bacterial species, no matter how smelly and undefined they are. Thus fecal transplantation has started to find its way into standard medical care.

In our small office my gastroenterology colleague was treating a very miserable elderly woman with recurrent and persistent C. Diff diarrhea. He had used all the appropriate antibiotics to treat it, all of the sweet smelling probiotics available, and still she cramped, she pooped, she had no appetite, she felt terrible. In fact, she was slowly dying. He recommended fecal transplant (also known as fecal flora reconstitution or fecal biotherapy.) She was game.

This is how it was done: The donor, usually a household or family member, donated the first morning bowel movement. The donor should be tested for parasites and blood diseases and is screened to make sure she or he has normal bowel habits. The recipient cleaned herself out by drinking the solution that we use prior to a colonoscopy, about a half a gallon of flavored polyethylene glycol solution. In a blender (which was subsequently thrown away) the BM was mixed with saline solution (not bacteriostatic) and then delivered in several portions as a retention enema. That's all.

Our patient was cured, just about immediately and so far completely. This is a very common result, according to the studies I have been reading.

Other techniques include instilling the solution by fiberoptic scope and by a plastic tube that goes through the nose and into the small intestine. There is no indication as to which technique works best.

At least one study also noted success in treating ulcerative colitis, a chronic inflammation of the bowel, with fecal transplant. It is far from standard treatment for this condition, however.

One of the most common bowel problems in my practice, leading to significant disability and work loss, is something called Irritable Bowel Syndrome (IBS). This condition causes no inflammation of the colon, just diarrhea and constipation, bloating, cramping and sometimes a sensation of incomplete emptying. Treatment of this condition usually involves avoiding foods that make it worse, bulking up the stool with fiber and occasionally taking medications that reduce bowel motility and cramping. Lately we have found that certain antibiotics sometimes reduce the associated bloating and discovered that the disease often follows a case of traveler's diarrhea, suggesting a bacterial cause. We have begun to treat irritable bowel with probiotic pills with some success. Is it not, perhaps, time to introduce healthy stool into patients with irritable bowel and look for cure rather than remediation?

Studies on obese humans and mice suggest that the bacteria in the gut is different than in their normal weight counterparts. In the case of mice, transplantation of bacteria from obese to normal weight animal results in weight gain.  Are we, in fact, attributing fault regarding weight maintenance to human will power, when that fault at least partly belongs to our internal flora?

Another bacterial community that is vulnerable to decimation by antibiotic use is the vagina. It is very common for my patients to develop an itchy yeast infection after use of any of the powerful antibiotics that I prescribe for urinary tract and other infections. I treat these with oral or topical antifungal medications to wipe out the yeast, but it is not unusual for a patient to continue to itch on and off for weeks even after treatment. Often we recommend use of healthy bacteria, such as found in yogurt, to improve the flora. We usually have our patients eat the yogurt, but sometimes recommend they use it inside the vagina. It seems more likely that reconstitution of a whole community of bacterial flora by way of a transplant from a healthy vagina would work considerably better.

I sense at least 50% of my readers may be stifling a gag reflex at this point, assuming that they have made it this far. I sympathize, and yet it hardly seems reasonable that squeamishness should be an important decision rule in determining good therapy.

Certainly these thoughts and trends are part of a very important thought shift in organized medicine. They represent an element of respect for the complexity of the human organism and recognition of the limitations of our use of the chemicals of pharmacology to treat disease. The tremendously complex and interactive community that we know as our own bodies deserves to be recognized as we move in the direction of improving the quality of health care.

Tuesday, August 2, 2011

More reasons why Medicare costs are too high: hospice care is grossly overpriced

Care of the dying is one of the most important jobs that a physician or nurse can have. Death, like birth, is a momentous and sacred transition, and good care can give peace and comfort to the patient as well as to his or her family and friends. The dying process is often painful and frightening and good, knowledgeable support can alleviate suffering for all involved.

Hospice care has evolved since its inception in the 1400s to embrace support of the dying both in designated facilities and in patients' own homes. Once a patient and his or her doctor have come to accept that a disease is terminal and that death is imminent (usually 6 months of expected life left) hospice care can usually be arranged to allow a patients last days or months to be as pain and anxiety free as possible, providing caregivers with the help and support they need. Hospice services usually include home visits by nurses and nurse's aids, medications for symptoms control, social worker visits, grief counseling, medical equipment needed for home care and coordination of treatment with the primary physician. Studies have shown that not only are patients in hospice care less expensive than ones with the same diagnosis who are treated with standard medical and curative care, but they often live longer.

Hospice providers are either non-profit organizations or, more commonly now, for profit agencies. Hospice care has gotten increasingly more accepted as physicians and patients have moved away from squeamishness about discussing and planning for death, and now costs Medicare over 12 billion dollars annually. That care, though, according to multiple studies, saves the American taxpayer lots of money compared to treating those patients with aggressive but ineffective treatment aimed at curing their disease.

It all sounds great. So what's the problem?

Hospice care is incredibly and unnecessarily expensive. How expensive? Really expensive.

A hospice patient of mine was alarmed when she saw a statement of what Medicare had paid for her hospice care and showed me her data. She had been placed on home hospice due to a chronic and progressive condition that appeared to be likely to result in her death. After several months of hospice, it became clear that she was, though very sick and incurable, stable and not yet dying. Hospice was discontinued, and she became a curious consumer. Hospice charges a monthly fee for their regular services plus hourly charges for visits by nurses, aids or therapists. Medicare paid her (for profit) agency between $7000 and $9000 monthly for this woman's hospice care. This consisted of a basal hospice fee of over $5000 plus visits by nurses charged at $191 per 15 minutes and nurses aides at $112 per 15 minutes. Nurse's aides usually make no more than $15/ hour in any job they can get, and nurses might make as much as $35/ hour if they are lucky.

This is just way too expensive. And it is positively ridiculous that Medicare pays this amount.

My patient also showed me an account of how much she spent on a private nurse after hospice was discontinued. For about the same amount of time that hospice had spent with her she had shelled out about $230 in a month.

The whole idea of hospice is that care aimed at symptom relief frees the doctor, patient and family of the need to engage in complex medical care that doesn't improve quality of life. This can be a creative and much less stressful type of medical care, with a very focused agenda. It involves very little expensive technology. It is, at its core, not very expensive. Where is all that money going? I'm not sure.

Cutting payments to hospice would lead to outraged wailing and tooth gnashing, and yet hospice astronomically overcharges for their services. We are very dependent on hospice availability at this point since the alternative (aggressive medical care at the end of life) is both more expensive and less effective.If threatened with a significant reduction in payments, many hospice providers would probably cease to do business, leaving us in a lurch.

This is yet another situation in which third party payment has resulted in costs far beyond what a reasonably prudent consumer would agree to pay. Awareness of the problem by physicians and patients can be powerful, but the very fact that such ridiculous excess is occurring so blatantly shows that something is very wrong with how Medicare and other insurance companies reimburse for services, undoubtedly resulting in many billions of dollars of true waste.

I am truly thankful for the kind and compassionate care that various hospice organizations have provided my patients over the years, and I would hate to see this service go away. The whole field of palliative medicine has made death just a little bit easier and has brought compassion and dignity to countless families. With costs as high as these, however, hospice may find that it prices itself right out of our nation's ability to pay.