paradigms, 127–33, 135
parecoxib, 227
Pauling, Linus, 76
Peabody, Frances, 212
peptic ulcer disease, 129
Pereira, Tiago, 112
personalized medicine, 114–15, 155
pharmaceutical companies, 134–36, 138, 140, 142, 146, 163, 175–76, 192, 196
academic physicians working with, 176– 77
in drug approval process, 18
off-label marketing by, 142, 145–47
thought leaders working with, 175–76
trials sponsored by, 136–40, 176–77
phenytoin, 145
physical examination, 210
physical therapy, 22, 24, 89, 201
Physician Payments Sunshine Act, 176
pioglitazone, 31
placebo effect, 16, 22–23, 25–27, 28, 29, 45
for complementary medicine, 26
ethics, deception and, 16, 26–27
physiology of, 23
of sham surgery, 22–23, 29
pneumonia, 65, 137, 191, 208
Pollan, Michael, 80
post-test probability, 210
practice guidelines, 196
based on trials with flawed data, 135, 136
conflicts of interest in, 140–42, 147
for hemoglobin A1c, 33
for intra-aortic balloon pump, 39, 40
for screening tests, 17, 18, 46, 55, 93–94
summaries of studies contradicting, 217–45
PREDIMED trial, 78–79
prednisolone, 234, 238
pregnant women, 86, 94, 95, 99, 107, 137, 219, 220, 226, 228, 233, 239, 242, 243
premature ventricular contractions (PVCs), 12, 32, 166
preoperative clinic, 179
prescribing practices: direct-to-consumer advertising and, 152–53
empiricism vs. reductionism, 154–55
off-label marketing and, 142, 145–47
pretest probability, 210
Preventive Services Task Force. See U.S.
Preventive Services Task Force recommendations
priming, 140n
progression-free survival (PFS), 37–38
propensity to adopt flawed therapies, 148– 57
act now, data later, 149–50
and basic science in education, 153–55
and direct-to-consumer advertising, 152–53
and financial incentives, 4, 14, 17, 18, 95, 133– 34, 141–42, 149, 155–56, 161, 175–76, 195, 213
and technology effect, 150–51
prostate cancer screening / prostate-specific antigen (PSA), 11, 16, 43–44, 46, 47, 49–51, 52, 53, 54, 55, 86, 94, 239
Ptolemy, 128, 131
pulmonary-artery catheters, 222, 230
pulmonary edema, 238
pulmonary embolism, 104, 196, 206–7
questioning treatment recommendations, 19, 24, 65, 196–200, 204
burden of proof and, 183–89
rabies, 112–13
randomized controlled trials (RCTs), 5, 101–3, 108, 110–22, 134, 162, 205–6
cluster trials, 150
conducted by impartial sponsors, 203–4, 206
cost of, 192, 205
design bias in, 118, 139
of diagnostic tests, 211
end points of, 162
error rates in, 115–19, 126
ethics of, 104, 117, 119
evidence complicated by, 115–21
for FDA approval, 142, 162, 178
funding for, 186–87
increasing enrollment in, 191– 93, 194, 206, 207
industry-sponsored, 136–40, 176–77, 195
of medical devices, 143, 186
meta-analyses of, 5, 115, 120– 21
physicians learning about, 196
premature termination of, 119–20
to prove causation, 121
registry-based, 192–93
of screening tests, 47–48
of treatments that seem obvious, 111–12
of treatments with large benefits, 112–14
unnecessary, 205– 14
unnecessary, in dire, rare, or unique situations, 206–9
vastly increasing number of therapies tested in, 190
rapid response team (RRT), 63–64
Reagan, Nancy, 200
Redberg, Rita, 144
reductionism vs. empiricism, 154–55, 165
reforming the system: burden of proof, 162, 183–89, 206
nudge principle, 191–93, 194, 206, 207
refusal to abandon ineffective practices, 91–93, 95
relative risk reduction, 102
renal artery stenosis, 241
renal-replacement therapy, continuous, 241
reports, promising, 4, 133–34
research, useless, 180–82
robotic surgery, 44
rofecoxib (Vioxx), 6, 227
rosiglitazone, 232
rosuvastatin, 235, 239
SAMPRIS study, 89–91
saw palmetto, 229
saxagliptin, 31
Scandinavian Simvastatin Survival Study (4S trial), 101–2
schizophrenia, 229
science: basic, in education, 153–55
vs. medical science, 131–32
scientific method, 11–12, 125, 126–27, 131–32, 157
scientific progress, 125, 130–31
scientific revolutions and anomalies, 127–32, 135
screening tests, 43–56, 70
future of, 55–56
goals and evidence for, 45–49
overdiagnosis due to, 49–51
population data for, 51–54
reversals for, 54–55, 86
serotonin, 154
sham surgery, 22–24, 29
shock, 242
cardiogenic, 39–40
septic, 141, 236
SHOCK II trial, 39
simvastatin, 101–2, 236
skepticism, 20, 24, 25, 26, 29, 42, 80, 140, 184, 186
sleep aids, 148
sleep apnea, 229
Slutsky, Arthur, 155
smoking, 44, 102, 129, 180–81
cessation of, 14, 181
lung cancer and, 105–6, 107, 108
spending, health-care, 134
spinal anesthesia and cesarean delivery, 95, 226
spinal-cord stimulators, 143–44
standardized patients (SPs), 152
standards of care, 13, 24, 33, 65, 81–83, 85, 188n
statins, 6, 14, 35, 89, 93, 101–2, 141, 142, 145, 165–66, 199, 200, 235, 236, 239, 242
stents, coronary, 3–4, 6, 11, 15, 20, 27–28, 29, 92, 130, 131, 156, 187, 217, 224, 227, 231, 232
stents, intracranial, 89–91
streptokinase, intrapleural, 226
stroke, 20, 88, 181
cholesterol level and, 34, 89
hemoglobin A1c and, 31, 34, 197
hormone replacement therapy and, 104
hypertension and, 13, 108
treatment of, 88–89
stroke prevention: antihypertensives, 13, 32
cholesterol-lowering drugs, 35–36, 89, 141
intra-aortic balloon pump, 41
intracranial stents, 89–91
Mediterranean diet, 78–79
multivitamins, 73
subjective end points, 20–30, 126
for anginal chest pain, 27–29
for arthroscopic knee surgery, 21–23
other than pain, 24–26
placebo effect for, 22–23, 26–27
of sham surgery, 22–24
for vertebroplasty, 15–16, 20–21
suffering, 8, 24, 95, 143, 200, 208
suicide, 51, 150, 245
Sunstein, Cass, 191, 192
superspecialists, 174–75, 209
surrogate end points, 30–42, 45, 126, 197– 98
bevacizumab in breast cancer, 36–38
blood pressure, 36n; cholesterol-lowering drugs, 34–36
hemoglo
bin A1c, 30–34, 36, 41, 197, 232
hospitalization, 40–41
intra-aortic balloon pump and cardiac output, 39–40
qualities of, 38
truth about, 31–34
suvorexant, 148
syncope, 191
systemic lupus erythematosus, 229
systems interventions, 57, 59–61
blood sugar control in ICU, 67–68
to decrease IV catheter infections, 62–63
door-to-balloon time for heart attack, 65–67
gown-and-glove precautions, 58–59, 60, 61, 63, 64n;
gray zone of, 64–67
Hawthorne effect and, 62
medical reversals of, 61–64
rapid response team, 63–64
science of, 67–68
single-center before-and-after studies of, 61–62
Tamiflu. See oseltamivir tamoxifen, 225
technology effect, 150–51
testosterone replacement, 132, 231
Thaler, Richard, 191, 192
thalidomide, 94, 107
thought leaders, 175–76
thrombocythemia, 227
thyroid cancer, 201
tissue plasminogen activator, 88–89
tocodynamometry, 242
translation failure, 132n
treatments: with large benefits, 112–14
obvious, 111–12, 166
trephination, 188
tympanostomy tubes, 219, 228, 231
unique cases, 208–9
urinary tract infection, 222
U.S. Food and Drug Administration (FDA) approval process, 77, 142–47
accelerated approval, 37, 142, 144–45, 185, 189
for bevacizumab, 37, 38, 185
Breakthrough Therapy Designation, 189, 189f;
burden of proof and, 185–89
criticisms of, 142, 213
evidence of drug efficacy, 185
for fenofibrate, 35
for inferior-vena-cava filter, 186
Institute of Medicine review of, 189
for intracranial stents, 89, 91
for medical devices, 143–44, 185–86
for niacin, 200
off-label drug marketing and, 142, 145–47
to protect desperate people, 207–8
randomized trials and evidence base for, 142, 162, 178
for vandetanib, 201
U.S. Preventive Services Task Force (USPSTF) recommendations, 45, 56
colon cancer screening, 48
mammography, 16–17, 48, 51, 55
prostate c
vitamin D supplementation, 74
vaccines, 95, 113, 200n, 218
valdecoxib, 227
vancomycin-resistant enterococcus (VRE), 58–59, 61
vandetanib, 201
vasodilators, 228
vertebroplasty, 6, 15–16, 20–21, 24, 27, 28, 90, 92, 166, 197, 217, 240
vestibular neuritis, 224
Vioxx. See rofecoxib vitamin D, 71, 72, 73–74, 100, 230
vitamin deficiencies, 75–76
vitamin E, 1, 92
vitamin/mineral supplements, 69, 71–72, 73–74, 75, 76–77
Warren, Robin, 129
wheezing, 25, 85, 238
white-coat silence, 196
Wingspan Stent System, 91
Women’s Health Initiative (WHI), 104
Xygris, 141
VINAYAK K. PRASAD, MD, MPH, is a practicing hematologistoncologist and internal medicine physician. He completed his training at the National Cancer Institute and the National Institutes of Health in Bethesda, Maryland. He is an assistant professor of medicine and public health at Oregon Health & Science University. Dr. Prasad’s research focuses on oncology drugs, health policy, evidence-based medicine, bias, and medical reversal. He is the author of more than 90 peer-reviewed articles in academic journals, including the New England Journal of Medicine and the Journal of the American Medical Association.
::
ADAM S. CIFU, MD, is a professor of medicine at the Pritzker School of Medicine, University of Chicago. He is a practicing general internist and teaches courses in clinical medicine and in reading and understanding the medical literature. He is the coauthor of a textbook on clinical reasoning, Symptom to Diagnosis: An Evidence-Based Guide, which is now in its third edition. He is a Master in the Academy of Distinguished Medical Educators at the University of Chicago.
* As you will see throughout this book, one of the great sports in academic medicine is to choose a name for your trial that can be reduced to a catchy, memorable acronym. In our careers we have seen not only CAST and LIFE, discussed in this chapter, but also NICE - SUGAR, CLEOPATRA , and our favorite, CABG Patch.
* We are only talking about hypertension. If you have heart failure, you really need your carvedilol or metoprolol succinate!
* In later chapters we’ll learn about other procedures that make people feel better but provide no real benefit. These examples will make you reconsider the whole “feeling better” issue.
* If you wonder why we are taking physical therapy for granted, you are catching on. Is physical therapy really better than just telling patients to exercise at home? Or maybe, do nothing at all? Seems like something worth testing, too.
* The HbA1c measures the percentage of hemoglobin, a normal component of our blood that has sugar attached to it. In people with normal levels of blood sugar, 3 to 6 percent of the hemoglobin is “glycated.” When the blood sugar is elevated, as in diabetes, this percentage goes up.
* Blood pressure is an interesting example. It is a surrogate because we usually cannot feel it and it is used as a stand-in for a host of dreadful cardiovascular outcomes. At extremely high levels, though, blood pressure can cause symptoms and thus becomes an objective, clinical end point.
* Monoclonal antibodies are proteins that bind to a specific target. Antibodies are naturally produced by our immune system to bind to foreign substances like bacteria. They can also be produced in the lab to deliver drugs to a specific substrate, such as cancer cells.
* The improved cardiac output was noted in early studies of the device, although more recent studies suggest that the pump might not even improve the surrogate.
* Many advertisements attest to the benefits of futuristic-sounding robotic surgery, but at least for prostate cancer, there is no good evidence that patients do better if a robot helps their surgeon.
* Ilana Löwy’s book Preventive Strikes: Women, Precancer, and Prophylactic Surgery (2010) provides a wonderful description of how screening got to where it is today.
* A terrific book on the subject of breast cancer screening is Mammography Screening: Truth, Lies and Controversy, by Peter Gøtzsche (Radcliffe, 2012).
* Most would argue that he was worse off having been screened. By having the screening test, he lived his final year of life as a cancer patient.
† This number also takes into account the fact that treatments are not universally effective.
* There was a small difference in the rate of acquisition of MRSA, but this finding was less convincing, since it could have been that the ICUs assigned to “gown and glove protocol” had much higher rates of MRSA before the study began. It was also not the study’s primary end point.
† Systems interventions in medicine go by many different names: systems innovations, quality interventions, and health-delivery interventions.
* In neither of these cases, however, has there been a rapid retreat from use of the intervention.
* Currently, the USPSTF also says there is insufficient evidence to argue for, or against, higher doses. Calcium and vitamin D probably do help older women living in nursing homes and those who already have osteoporosis.
* For a terrific recent discussion of the regulation of “conventional” and “alternative” therapies, we point you to Paul Offit’s book Do You Believe in Magic? (HarperCollins, 2013).
* The trial enrolled men between 55 and 80 and women between 60 and 80, who had either d
iabetes or three cardiac risk factors.
* Giving credit where credit is due, we should point out that Medicare’s stance toward intracranial stenting was a prudent one. Medicare only funded the procedure in the context of clinical research testing its efficacy.
* This issue gets complicated when you ask, The cost to whom? To the patient? To the insurer? To Medicare?
* Countries with nationalized health care frequently produce very successful cohort studies. It has been said that every time someone sneezes in Sweden, someone writes it down.
* The word paradigm has since become one of the most abused terms in all of science.
* Honestly, it is often hard to decide what to call a revolution and what to call an anomaly that has a greater-than-average impact on the prevailing paradigm.
† For this discovery, Drs. Marshall and Warren received the Nobel Prize in Physiology or Medicine in 2005.
* In the medical literature this is often called translation failure.
* Of course, McKinlay did not use the term medical reversal.
* These data do suggest that as we go forward, tests for influenza should probably be used more regularly.
* The other problem with the study is the use of priming. Priming means that people give you the answer you told them to give. At a simple level, it is the difference between asking, “What color was the car?” versus “The car was white, wasn’t it?” In the study by Kesselheim and colleagues, a close look at the methods reveals that three times, prior to the survey, doctors were reminded that the study they were participating in was “not associated with any pharmaceutical manufacturer.” This repeated mention of funding source arguably primed readers to be more vigilant about the funding source of research. In a way, Kesselheim and colleagues may have inadvertently sown the seeds for the results of their study in their repeated insistence that it was not industry funded.
* This fee was likely much smaller than the profits reaped through off-label promotion— in other words, not large enough to truly serve as a disincentive.
* The nonbenzodiazepine hypnotics are the newest and most successful sleep aids presently on the market. Eszopiclone (Lunesta), one of these drugs, earned about $225 million in the fourth quarter of 2013 alone. A recent meta-analysis showed that, on average, these drugs get you to sleep only about 22 minutes faster.
* Increasingly, patients are being called consumers or clients, and doctors are called providers. These are terms we have assiduously avoided.
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