Ending Medical Reversal

by Vinayak K Prasad

  Because our work grows out of our clinical lives, we fill this book with anecdotes. All of these are composites of patients for whom we have cared. None of them is based on any single person, or even on one or two patients. Instead, they draw upon our general experience taking care of many patients.

  Medicine practiced well is beautiful. As a human pursuit, it is pure— caring for the suffering. Empathy and the ability to anticipate a patient’s changing needs are the hallmarks of an excellent physician. Clinical medicine can also be one of the most satisfying of intellectual pursuits. The diagnostic process and development of an effective management plan, when done well, are elegant in their thoughtfulness and parsimony. The fact that this intellectual activity is only a means to a greater end makes it even more magnificent. Conversely, medicine done poorly is painful to watch and worse to experience. It may lead to bad patient outcomes—unnecessary suffering and even death. Even practice that is only average creates anxiety for patients and doctors and runs up enormous costs to society. In the end, our goal in writing this book is to see more medicine done well and less done badly. Such a change would benefit patients, doctors, and all of us who pay for our health care.

  PART 1 MEDICAL REVERSAL :: EXAMPLES, FREQUENCY, AND CONSEQUENCES

  1 WHAT IS MEDICAL REVERSAL?

  WE EXPECT THAT MEDICAL THERAPY will change and evolve with time. Good treatments will replace bad ones, and then better ones will replace those. Antibiotics have replaced arsenic, and anesthesia has replaced a bullet held bracingly between the teeth. Recently, however, change has occurred in surprising ways. If you have followed the news about prostate cancer screening, mammography for women in their forties, hormone replacement, cholesterol-lowering medications, and stents for coronary-artery disease, you might think doctors cannot get anything straight. These common practices were not replaced by better therapies; they were found to be ineffective. In some cases, they did more harm than good. You might be worried that some medical practices are nothing more than fads. In some cases, you would be right.

  We call this phenomenon “medical reversal.” Instead of the ideal, which is replacement of good medical practices by better ones, medical reversal occurs when a currently accepted therapy is overturned—found to be no better than the therapy it replaced. Now, you might argue that this is how science is supposed to proceed. In high school, we learned that the scientific method involves proposing a hypothesis and testing to see whether it is right. This is true. But what has happened in medicine is that the hypothesized treatment is often instituted in millions of people, and billions of dollars are spent, before adequate research is done. Not surprisingly, sometimes the research demonstrates that the hypothesis was incorrect and that the treatment, which is already being used, is ineffective or harmful.

  CASES OF REVERSAL

  A few people’s stories highlight notorious examples of reversal in medicine. Consider Samuel Jones, a 57-year-old gentleman who had a heart attack in 1991. He was admitted to the hospital and treated with the standard medical regimen, which, at the time, included flecainide, a drug used to stabilize his heart rhythm. In the late 1980s and early 1990s, flecainide and its sibling drugs were widely used with the intention of suppressing extra heartbeats (called premature ventricular contractions, or PVCs) and preventing death. The logic behind the use of these drugs was ironclad. PVCs are strongly associated with sudden death. The more you have, the more likely you are to die. And there was no better medicine for suppressing PVCs than flecainide. How could it not save lives? Some cardiologists were so confident in the drug that they would not let their patients enter studies of this medication. Such studies required that some patients be randomized to receive a placebo instead of flecainide. In all good conscience, how could they risk having their patients deprived of this life-saving drug?

  Unfortunately, flecainide did not work. In 1992, a large study called the Cardiac Arrhythmia Suppression Trial (or CAST trial) showed that flecainide, as well as a similar drug, decreased PVCs as expected but also increased patients’ chance of dying.* The finding was devastating. It changed not only how we treat heart-attack patients but how we evaluate medical therapies altogether. CAST taught us that even the most careful reasoning and the best scientific models do not guarantee an effective clinical treatment. What works in the lab, or on a computer, or in the head of the smartest researcher does not always work in a patient.

  But now, more than 20 years later, this is a lesson that many physicians and leading researchers still have not really learned.

  Let’s consider another medication, this one for high blood pressure (hypertension). Hypertension remains one of the most common ailments in America. Although most people with hypertension are entirely without symptoms, there is no doubt that hypertension strongly predicts an increased risk of stroke, heart disease, and death. It is truly a silent killer. People with naturally lower blood pressure live longer, and people who use certain medications to lower their blood pressure can decrease their risk of death. One of the first drugs used to treat hypertension was atenolol. Atenolol, a member of the beta-blocker class of antihypertensives, dramatically lowered blood pressure, and for decades it achieved the rarefied status of “trial standard,” meaning that you had to show your new drug was as good as atenolol in order to get it on the market.

  In 2002 something really unsettling (or maybe even terrifying) happened. After atenolol had been used to treat hypertension for nearly 20 years, the results of the LIFE trial were published. This trial compared atenolol to a newer drug, losartan. People who took losartan had fewer strokes and lived longer than those that took atenolol. At first glance it seemed that we had come up with a better antihypertensive; this seemed like an example of replacement. Somewhat surprising was that both drugs lowered blood pressure the same amount.

  The question was, did losartan beat atenolol because losartan is better or because atenolol is actually ineffective? The tantalizing finding in the LIFE study was extended in 2004, when a pooled analysis of all people who took atenolol versus sugar pills (placebos) in trials showed that atenolol was no better than the placebo. Atenolol did lower people’s blood pressure, but it did not decrease people’s risk of dying or of having a heart attack. Let that sink in. A drug that was widely used, accepted as the standard of care, had made millions and millions of dollars for its manufacturers, and had made high blood pressure the subject of dinnertime conversation, did not make you live a single day longer. A recent study showed that metoprolol (another beta-blocker) is no better than atenolol. If you have taken a beta-blocker for high blood pressure, you may have shaved a few percentage points off your risk of stroke, but you did not extend your life. In the world of blood-pressure medicines, you took a pill that does not work.*

  If the only place modern medicine erred was with medications, we would be fortunate. But there are also medical procedures, some used for decades by practitioners who have reaped huge financial rewards, that have been shown not to work.

  Let’s examine another person. Anthony Baker is a 55-year-old mechanic who thinks of himself as active. His job in a garage requires him to be on his feet most of the day. In the summer he mows his lawn every week—with a push mower, no less—and in the winter he shovels snow from his walk after storms. Anthony does not have any health problems—well, at least that he knows of—and he sees his doctor yearly. At his last checkup, he was told that he was in fine health, aside from the yearly advice to quit smoking.

  Over the past few months, however, Anthony has noticed that when he exerts himself, he feels an ache in his chest. This “pressure” resolves after about five minutes of rest. Anthony calls his doctor to tell him about the chest tightness. His doc is concerned that Anthony might have developed coronary-artery disease and that his symptoms represent angina.

  Angina is cardiac pain that occurs when the heart’s demand for oxygen outstrips its supply. It often happens during exertion because that is when the demand for oxygen is greatest. Anthony’s d
octor orders a stress test, a test that examines the heart’s function during exercise. The test shows that Anthony has a narrowing in his circumflex coronary artery (one of the three coronary arteries that supply oxygenated blood to the heart). Based on the results of the test, the doctor diagnoses Anthony with coronary-artery disease, tells him to stop smoking, starts him on a few medications (metoprolol, a beta-blocker, to lessen the heart’s oxygen demand; atorvastatin, a cholesterol-lowering medication; and aspirin). He also schedules him to see a cardiologist the following week.

  When Anthony sees the cardiologist, he has not yet started his medications and reports one episode of chest pain that occurred while he was walking his dog over the weekend. The cardiologist schedules Anthony for a coronary angiogram. During an angiogram dye is injected into the coronary arteries to assess their patency—to determine whether or not there are blockages. The angiogram shows a 90 percent blockage of his circumflex artery. During the procedure the cardiologist places a stent, a metal tube, in the artery and the 90 percent blockage disappears. He gives Anthony another prescription, this one for clopidogrel, a blood thinner, to add to the rest of his medications.

  One week later Anthony sees his regular doctor and is pleased to say that, despite having shoveled six inches of snow the previous day, he is feeling the best he has felt in years. He has no pain and, in fact, he recognizes that he was probably having more chest symptoms than he was aware of before the procedure.

  So, was Anthony cured by the cardiologist? It is undeniable that Anthony feels better.* You may also be thinking that Anthony narrowly made it— that if he had not had the artery opened, he would have had a heart attack. That because of the stent, Anthony will live longer. And though the procedure cost more than $10,000, on the whole, it must be worth it.

  But what if we told you that Anthony is no less likely to have a heart attack. What if we add that Anthony will not live a single day longer. And, perhaps, most concerning, what if we tell you that in 12 months, Anthony’s chest pain will be the same, even though he had the stent. Did Anthony really benefit?

  There is a long list of medical procedures whose use is based on scientific evidence that is, at best, suspect. Vertebroplasty is another great example. For years, doctors struggled to treat people (mostly women) who suffered osteoporotic fractures of the spine. These fractures can lead to chronic back pain. In the late 1990s, a couple of radiologists had a brilliant idea. Why not insert a needle into the fractured bone and inject medical-grade cement. The theory was that the cement would plump up the bone, the nerves would get some extra breathing room as the fractured bone was lifted away, and the pain would dissipate. When these pioneers performed the procedure, vertebroplasty, on a few dozen patients, they were amazed with the results. Patients immediately felt better. Patients and doctors were convinced.

  In the very early 2000s, interested parties lobbied Medicare to pay for vertebroplasty, and their request was granted. In a few years, tens of thousands of people were having the procedure each year. By the end of the decade, vertebroplasty was a billion-dollar-a-year industry. There were complications—rarely, the cement would go somewhere it was not supposed to—but on the whole, this procedure seemed like a real advance. In 2009 two groups of brave investigators put vertebroplasty to the true test. They enrolled 200 patients. Half of the patients got vertebroplasty; the other half were taken to the procedure room and prepped for the procedure; the cement was opened, so patients could smell it; and salt water was injected. Both groups of patients, those that got vertebroplasty and those that had a sham procedure, had identical improvements. Vertebroplasty, as it turned out, is no better than a placebo.

  This outcome alone may not convince everyone that vertebroplasty is a bad thing. Who cares if the effect is “in your head,” as long as it works? Some with expertise in the placebo effect would hold this position. Although vertebroplasty was no better than a sham procedure, either may very well be better than doing nothing. In this book we examine other interventions that claim to decrease pain but perform no better than a sham procedure. In many cases, both are better than doing nothing. What does this mean? There is something about the acts of a medical intervention— the thoughtful counsel of the doctor, the skilled support of the nurses and staff, the psychological comfort of acting—that collectively make us feel better. The downside is only that the procedure is costly, may involve risk (either because of the procedure itself or by delaying an intervention that has intrinsic benefit), and involves deception. The question then becomes, Can we reap the benefits of placebo treatments without the deception, the risk, and the cost? In chapter 2 we discuss the placebo effect in more detail. For now, let us at least agree that the money spent on the cement used in vertebroplasty—often thousands of dollars per procedure—was wasted. Salt water would have sufficed.

  When medical reversal involves pills or procedures, it affects patients unlucky enough to have an illness and be prescribed a faulty therapy. When reversal involves prevention efforts and screening campaigns, millions of healthy people can be affected. In the past five years, two major public health efforts, breast and prostate cancer screening, have, to a large extent, been overturned. Let’s consider mammography.

  In 2009 the U.S. Preventive Services Task Force, generally considered the most impartial of the hundreds of groups that produce guidelines for physicians to follow in their clinical practice, changed its recommendation on whether women in their forties should undergo screening mammography. The old recommendation was to do a mammogram in this age group every other year. The new recommendation is not to do it at all.

  This reversal made a lot of people very angry. An article from November of that year in the Seattle Times had the provocative title “Mammogram Mania: Risking Lives or Dollars? Physicians’ Community Speaks Up, against New Recommendations.” Radiologists, who had the most to lose (at least financially), protested the loudest. They accused the task force of trying to save money instead of lives.

  Was any of this a fair characterization? Were the changes to the guidelines a shock? Not to those who had followed the medical literature. The truth is that the guideline change was three years in the making.

  In 2006 a huge study on exactly the question of mammographic screening for 40-somethings was published in Lancet. More than 160,000 women in their forties were randomized to mammography screening, or not, and they were followed for, on average, 10.7 years. It is worth pausing to consider just how impressive a feat this study was. The study authors got more than 100,000 women to participate in a study of a medical treatment that required yearly visits for over a decade. For reasons we discuss later, as far as evidence in medicine goes, this is about as good as it gets.

  The authors of the trial found that there were fewer deaths from breast cancer among the women who received mammograms, compared to those who did not, but this difference did not reach statistical significance. In other words, the difference was so small that we cannot be sure the difference was not due to chance alone. What this means is that a few women who got mammograms died of breast cancer and a few women who did not get mammograms also died. Neither group had more women who died of breast cancer.

  If you look at the study for what is truly important, dying, from any cause, not just breast cancer, you find that the death rate was identical in the two groups. Therefore, we should not screen these women with mammography, because in the history of medicine no one has ever shown that doing so saves lives. In aggregate. On the whole. Regardless of the financial impact.

  Put another way, what if all the women in their forties of Washington, D.C., got mammography and all the women in their forties of Chicago did not. Well, nearly all the women in this age group in both cities would be alive at 50, and a few unlucky ones in each city would have died of breast cancer. And all the statisticians at the NIH in Bethesda, Maryland, and at the University of Chicago would be hard-pressed to say for certain which city got mammograms if you did not tell them. If the statisticians looked
at death rates for 40-something women in both cities, they would be identical.

  What led to all the hand-wringing about the guideline changes was not the reversal of screening mammography; it was that doctors had recommended mammography for women in their forties for all those years. A costly, ambitious medical program was conducted on a national level for years before we had data that said that it worked. What we know for sure is that because of false-positive mammograms and a phenomenon called “overdiagnosis” (more in chapter 4) the program gave many women a cancer scare, a needle biopsy, radiation exposure, surgery, or worse.

  We believe that reversal is the most important problem in medicine today. When we doctors flip-flop on our advice to patients, it usually is not because the treatments stopped working. It usually is not because someone discovered a harm no one had previously noticed. It is usually because the practice never worked—we were wrong all along. We promoted it before we had properly studied it. We knew it had some harms, sure, but we never thought it lacked benefits. This problem underlies people’s distrust of the medical establishment and is a very important reason that health-care costs are soaring without any improvement in people’s health.

  Now reversal is not the only problem in medicine, but it is a common channel through which many of the problems run. Yes, pharmaceutical companies manipulate data to get drugs and devices approved and used. Yes, physicians overtest and overtreat for fear of malpractice suits and because of the financial benefits that this behavior brings. Yes, hospitals and clinics market tests and treatments that offer little benefit because they believe they will attract well-insured patients. However, if we find a solution to the problem of medical reversal, a way of preventing the use of therapies that do not work, many of these other problems will cease to exist.