They all sound good at first. A decade later they don’t sound so good.

Human recombinant activated protein C (HR APC; drotrecogin alfa; Xigris) addresses the pathophysiology of sepsis. It is low in sepsis and associated with death. Replacing it should work. So a randomized trial was done in 2001 (http://bit.ly/vQ0f5B) showing that it decreased mortality (from 31% to 25% at 28 days) with a small increase in serious bleeding (2 to 3.5%, p=0.06). In the US, the FDA approved it.  Subsequently a retrospective study finds substantial bleeding risk. Then 2011 brings a similarly sized trial (n=1696) finds no mortality benefit and it is withdrawn from the market (http://1.usa.gov/vwQXtc).

 Nesiritide is a vasodilator that addresses the pathophysiology of heart failure. It should work. So a randomized trial was done showing improvements in physiological parameters and dyspnea at 3 hours (http://bit.ly/sl1yRi). Another trial found similar improvements in symptoms (http://1.usa.gov/vjYReu). In the US, the FDA approved it in 2001. In 2011, a much larger trial (n=7141) found no effect on dyspnea or heart failure rehospitalization, and a doubling of hypotension (http://bit.ly/sW5oRV).

 So even if they don’t work at least they cost money and cause harm…

 What happened? In both cases these were “pivotal” trials—single studies after which governmental approval followed and changed clinical practice. In the case of APC, the early trial was stopped prematurely for benefit.  We know this risks overestimation of benefits.  In the case of nesiritide, an early (small) trial did not find (or look for) important clinical outcomes. The second one did.

 In retrospect the drugs should not have been approved or used widely.  The evidence was insufficient. Maybe these were just mistakes, and now the lessons regarding appropriate interpretation of evidence have been learned.  But I don’t think so.

 I am not sure we will ever learn. Why? Because of how we are wired and how we understand things.  First, we want to help.  We want treatments that work, particularly for bad common diseases like sepsis and heart failure. Second, we find new treatments that can fix the physiology that has gone awry. We believe they will work and we take any supporting evidence we can get. Once we have it, we are not easily dissuaded (for examples see last blog re breast and prostate cancer screening (http://bit.ly/tk4i1j), or consider the evidence that shows intensive glucose control has little if any benefit but plenty of risk (http://bit.ly/w3nqx6), and evidence that finds the risk of pre-hypertension cannot be identified yet treatment is recommended (http://bit.ly/va9w9w).

 We become confident that we know what works, and when facts conflict with our expectations we ignore them (see a superb discussion re: the Surety of Fools by Daniel Kahneman who coined the term “the illusion of validity” (http://nyti.ms/t6qihi).

 Lets see how the latest information on bisphosphonates, drugs that decrease fracture but are now known to also increase fractures is handled…(see EBM online http://bit.ly/rGi5cg)

Does Belief-based medicine trump EBM? breast and prostate cancer screening recommendations redux

It has been an exasperating couple of weeks and there will be more to come. I got my coffee and sat down, thinking I could rest a bit and gather strength for the day while a grand rounds speaker droned on. But then it happened—the radiology professor began to build her case for screening all women 40-49 years of age for breast cancer.  She spoke as if her case was airtight. She was about to be surprised by audience reaction. The US Preventive Services Task Force (USPSTF) had gotten it wrong she implied, and we are still reeling from it two years later. They shouldn’t have changed their recommendation.

In 2009, the USPSTF revised its recommendation.  Here it is (http://bit.ly/aJJ6O7):

“The USPSTF recommends against routine screening mammography in women aged 40 to 49 years. The decision to start regular, biennial screening mammography before the age of 50 years should be an individual one and take into account patient context, including the patient’s values regarding specific benefits and harms. (Grade C recommendation)”

“C” means: “There may be considerations that support providing the service in an individual patient. There is moderate or high certainty that the net benefit is small.”  It does say “recommends against” but also says to consider values about benefits and harms.  Seems reasonable doesn’t it?

The speaker went on: Since screening was implemented breast cancer mortality has declined. Screening detects early stage tumors, those we can treat before they get worse. And young women get breast cancer, the really bad aggressive kind. At our hospital in the past 3 years, some 79 women in that age group were diagnosed with cancer. And the USPSTF doesn’t think we should screen them all. These are young women with families and jobs. They don’t even want us to recommend women do self-exams. Unbelievable.

A few colleagues rumbled. They asked “Was the decline in mortality due to screening?” “Were the 79 detected by screening?” Fair questions but peripheral, I thought. I felt it coming. I boiled over with “What proportion of women screened versus not screened die from breast cancer? Shouldn’t that be the starting point for the discussion?” The conference ended without an answer though impressive sounding relative risks were presented.

A particularly insightful colleague pointed out that while we might want to know the numbers I asked for, that patients might have trouble understanding them, and more importantly, even when they did understand, they had little context for decision-making. They might be anxious and just want to know what they should do.  “What would you do?” or “What do you think I should do?” they would ask their doctor.  I had gathered strength for the day, not by snoozing through a lecture but by being energized about the battles between evidence-based medicine and whatever the alternative is.

This was the week after the USPSTF had downgraded its prostate cancer screening recommendation to recommending against it (a Grade D recommendation: means they discourage use of the test because there is moderate to high certainty that it has no net benefit or that harms outweigh the benefits).  http://bit.ly/q0Lkyv

A US presidential candidate condemned the recommendation. http://nyti.ms/mZg9kQ  And a CEO of a group devoted to ending prostate cancer said that the recommendation “condemns tens of thousands of men to die this year and every year going forward…”  http://bo.st/pPaCQg

Seriously? People who spent months to years reviewing the best evidence did that?  Here is the evidence: One trial found a 0.07% decrease, another a 0.03% increase, and a meta-analysis, no difference in prostate cancer deaths attributable to screening. And yes, those zeroes and decimals are in the correct places. And harms abound.  There was a voice of reason in a physician-written editorial to the New York Times that addressed both breast and prostate cancer screening. http://nyti.ms/poNJ5i

So what is going on?
Belief is powerful. We believe in pathophysiology, and well we should.  Early stage tumors become late stage tumors.  Sometimes early stage tumors can be removed and the later stage ones prevented.  Though inconvenient, it also turns out that in some cancers (eg breast) early stage tumors are manifestations of an already systemic disease, and in others (eg prostate), tumors may not cause harm during the patient’s lifetime. Screening might not help those.

Memory is powerful (the availabity heuristic). We remember the young man or woman who died a horrible cancer death. It was a cancer we had a test for. And we hadn’t tested for it. Their family might complain that they hadn’t been tested. A colleague pointed out to me that no patient had ever complained about getting screened.  Even when they suffered all of the downstream consequences (eg surgical complications, erectile dysfunction, incontinence) they were grateful for having been saved (of course one doesn’t know whether he would have been saved without intervention or complications).

The ecology of health care first described in the 1960s by Kerr White continues to be ignored. http://bit.ly/mQdULM Most people do not end up in the care of hospitals or specialists. Yet those who view healthcare through a tertiary care lens are often the most respected, influential and vocal promoters of what should be done for populations and patients in primary care settings, where they have no expertise.  (others with no discernable expertise in this arena include politicians, yet they speak loudly). The USPSTF starts its recommendation process with a systematic review of the evidence. Experts such as those on the USPSTF do us a great favor by examining the evidence underlying preventive care practices from the perspective of populations and patients without disease.

Finally, there is the belief that doing something is always better than doing nothing.  Suffice it to say that isn’t true. But doctors, patients and people have a hard time with it. It is tiresome to keep hearing that a common bad disease is sufficient information to justify doing something, even when evidence is absent it works, or even worse, when evidence finds harm. “How can you just sit there doing nothing?”

So what should we do?
Despite complaints about evidence-based medicine, I have yet to hear good arguments about why we should ignore high quality evidence or not be explicit when there is an absence of evidence. And like democracy, evidence-based medicine may not be perfect but it is the best we have. Basing clinical practice primarily on pathophysiology, belief and the most recent bad outcome is not a viable alternative.

But while evidence can be very informative, we have a long way to go towards getting it understood and easily used.  We need to communicate the evidence accurately and dispassionately to patients in ways that it is accessible to them (which may vary by patient) and at times when they can be receptive.

At age 40, a woman’s chance of dying from breast cancer is 3% (5-year risk if no risk factors is 0.4%, and up to 6% or more if risk factors are present). http://bit.ly/pi2cNq Screening during ages 40-49 reduces that chance by 15% (95% credible interval 1%-27%), to 2.55% (a 0.45% decrease and up to 56% of women will experience a false positive. Because not everyone adheres to screening, the number needed to screen to prevent a breast cancer death even in clinical trials is 1904 (see USPSTF evidence report; google it). A model for communicating this type of information visually with patients can be found here http://bit.ly/pyqqbR

For prostate cancer, the lifetime risk of dying from it is 2.8%, most after age 75. The benefit of screening remains uncertain but one trial puts it at a 0.7% absolute risk reduction for prostate cancer specific mortality (eg to 2.1%); 80% of PSA tests are false positives (and that doesn’t consider the fact that most actual cancers wont lead to death), 20% will get a biopsy (in 10 years of screening), and 20-30% of men treated for prostate cancer with surgery or radiation will have incontinence or erectile dysfunction.

We also need to offer patients our best medical judgment based on that evidence, taking into account what we know about them—best done by a clinician who has comprehensive knowledge about the patient and is in a longitudinal trusting relationship with them. Easier said than done, I know.

“OK, OK. Whatever,” you might say, “but what will you do?” Hopefully you don’t really care what I would do, at least not as a guide for your practice. But, I’ll tell anyway.

Some of my patients want me to prove they don’t have disease. I tell them I cant do that but they know there are tests that can detect diseases. These patients often think that when I send a blood test, I am checking them for “everything.” I will continue to explain to them that it doesn’t work that way, but in the end, so long as they understand the consequences of testing, I will order the mammogram for the 40-year-old. Prostate specific antigen testing I will reserve for those who are otherwise un-persuaded after I inform them the test likely causes more harm than good and is not recommended, and they request and consent to testing; but I can still order it in those rare cases with a good conscience and consider it good medical practice because I know some cancers will be detected and cured only as a result of testing, even if the odds are strongly against it being the case for this one individual.

I have other patients who say “que sera, sera” or “if it ain’t broke, don’t fix it.” They are not convinced that screening is worth it (after being presented with data in an understandable way). Respecting their values and autonomy, I wont test them.

The patient in the middle ground is the most difficult and perhaps most common.  For prostate cancer I will follow the USPSTF guidance against screening. But I will provide numerical information to patients when they are interested. For breast cancer, I will have a low threshold for offering screening to women age 40-49 years as long as they understand the 50% or so chance of false positives (and attendant anxiety, repeat imaging, biopsy and other procedures unnecessary only in retrospect) and still deem it worthwhile to them.

This past week the USPSTF released its recommendation that cervical cancer screening be started later (age 21) and be done every three years (or not at all after smears are negative 3 times in a row). There is another presidential debate today in the US; probably this will come up. It’s going to be another energizing week…

A writer at the Boston Globe is annoyed by the terms “evidence-based medicine” (and “reality-based community” and “fact-based presidency,” among others that he calls verbal tics).  Surely these terms have become overused. But they have become overused because people want to base decisions in evidence.  But the reporter scoffs at the BMJ (and the journal EBM) by quoting the long-accepted (since around 1992) definition of EBM and mocking it.

About “evidence-based medicine” he asks, “As opposed to what?”, making the same mistake many learners make when they first hear about EBM. He believes the practice of medicine must all be evidence-based and is unaware that anything else could go on, or that it might be complicated to identify and apply evidence. Clearly EBM (the practice and the journal) is about using the best evidence.

Anyway, the reporter’s piece and my response can be seen here…as per my tweet earlier today “EBM and BMJ taunted by Boston Globe writer http://t.co/liNMZMx last week. EBM responds…See it in the Globe today http://t.co/Uo77Yss ” and follow me @EvidBaseMed_BMJ

Expert opinion and observational studies have favored lung cancer screening but trials (of plain xrays) have not shown benefit, until now. For years, many have been asking for a randomized trial. Now that the results of the (US) National Lung Screening Trial (NSLT) have been published, it reminds me of the admonition to “be careful what you ask for, you just might get it.”

The randomized trial compared three screenings, either low dose CT scans or plain chest radiographs and adherence to the screening protocol was >90%.  How to address a positive test was left to clinicians outside the trial. It enrolled 53 454 participants age 55-74, who smoked at least 30 pack-years currently or who had quit in the past 15 years, and had not had lung cancer or a recent chest CT scan, hemoptysis or unexplained weight loss. The authors estimate only 7% of US current or former smokers would meet these criteria. So the study results do NOT apply to 93% of smokers. One wonders though, to whom they will be applied (paying customers?).

What were the results? Amazingly, despite the publication source (New England Journal of Medicine, http://bit.ly/qKs6Lq) and widely agreed upon reporting guidelines, the main results are presented as relative reductions, making them seem large (a 20% decrease in death from lung cancer). I don’t mean to minimize though, just to be clear—it is important that there was a reduction, and more lung cancers were diagnosed in the (low dose) CT group, which had fewer lung cancer deaths. The absolute reduction was the difference between 356 lung cancer deaths in 144,103 person-years in the CT group and 443/143,368 in the plain x-ray group. The absolute risk of lung cancer death among those screened at least once was 1.3% in the CT group, 1.6% in the x-ray group, an absolute risk reduction of 0.312%, for a number needed to screen with 3 tests of 320 to prevent 1 lung cancer death over 7 years. Overall mortality was also reduced (by 0.5%). Complications of evaluation of a positive test were 1.4% in the CT group, 1.6% in the x-ray group.
The vast majority of positive tests were false positives (96% in the CT group, 95% in the x-ray group).

None of this addresses long term cumulative population harms from radiation exposure or any impact on likelihood of quitting smoking.

What to do? Many may reach different conclusions depending on the presentation of the results. Others will take these results and then add patient values and preferences. Others still may wish to wait to see the cost effectiveness analyses.

What will you do? You now have the evidence…

Pharmaceutical company advertisements (at least in the US) dutifully list a litany of side effects and other risks after presenting their benefits. Package inserts and many drug reference materials for health professionals do the same. The written lists are exhaustive and the print small, and in audiovisual ads the lists are read aloud faster than a seasoned auctioneer can run through bids. The drug makers are doing what is required of them by regulatory agencies. But the information is not usable by patients or even clinicians. Wouldn’t it be nice if patients and doctors could find the information they want and need easily? For example, how well does the drug work? What are the main side effects and risks and how often do they occur?

Woloshin & Schwartz propose a simple solution. Information boxes on medications similar to those on bags of potato chips or cereal boxes. But these boxes would clearly state outcomes of randomized trials quantifying results in medication versus placebo groups (e.g. absolute risks). Patients (and doctors) would then have information they can use when making decisions. A simple idea, with evidence in the literature already to support it. Their advice to the US Food and Drug Administration appears in today’s New York Times http://nyti.ms/mt2KHr Here at Evidence-Based Medicine, I would welcome papers on other innovations in communicating evidence to patients, and clinicians.

Welcome to the start of an occasional blog from the journal Evidence-based Medicine (http://ebm.bmj.com/). In this blog, you’ll find issues of interest to those practicing and teaching evidence-based medicine (EBM).

At the journal each week, the associate editors and I review a long list of articles (click on “EBM Long List” on the home page).  The list is generated by systematic searching of peer-reviewed journals most likely to contain articles of relevance to primary care and general medicine practice that meet basic validity criteria (http://ebm.bmj.com/content/16/2/e1.extract).  We then choose the top three selections based on validity and relevance/impact.
Look for critical appraisal and commentary on the top 3 in an upcoming issue of the journal. This week the top 3 are:

Wells G et al. Cardiac resynchronization therapy: a meta-analysis of randomized controlled trials. CMAJ 2011; 183: 421-429.  This systematic review suggests the evidence for cardiac resynchronization and implantable defibrillator therapy for patients with heart failure is robust. One might raise questions regarding benefits about subgroups (e.g. older patients or those with comorbidity).

Gerstein HC et al. Long-term effects of intensive glucose lowering on cardiovascular outcomes. N Engl J Med 2011; 364: 818-828.  Long-term results from this trial find increased mortality from intensive glucose control among those with type 2 diabetes.  One wonders how many such trials will be needed to temper the zeal with which glucose control is sought among all patients.

Connolly SJ et al. Apixaban in patients with atrial fibrillation. N Engl J Med 2011; 364: 806-817.  A randomized trial adds another alternative to vitamin K antagonists for a-fib, for patients unsuitable for or unwilling to take warfarin. It will be of interest to see how this alternative fits in with other non-warfarin options now available in terms of costs, risks, and efficacy.

Some articles didn’t make the cut, mainly due to less direct, immediate or widespread relevance to practice.

**A systematic review in JAMA (2011; 305: 913-922) suggests that antihypertensive treatment can decrease cardiovascular disease and death for people without hypertension but with heart disease. The review raises the question of efficacy for those without hypertension or heart disease.
**A randomized trial (Lancet 2011; 377: 823-836) suggest that among those receiving specialist care for chronic fatigue syndrome, that cognitive behavioral therapy and graded exercise therapy have modest efficacy.
**A double-blind randomized trial in the hospital found that high and low dose, and bolus and infusion of diuretics led to similar symptom and renal function outcomes of acute heart failure (N Engl J Med 2011; 364: 797-805).
**In a trial of olmesartan, the medication appeared to delay microalbuminuria but increased fatal cardiovascular events for those with heart disease (N Engl J Med 2011; 364: 907-917).
**Finally, ultrasound had surprisingly poor sensitivity (and specificity) for nonpalpable cryptorchidism in a study that compared it to surgical exploration results (Pediatrics 2011; 127: 119-128).