Results of the SPRINT trial

Not sure what the hullabaloo is all about. Some doctors seem to be jubilant that the SPRINT trial shows lower blood pressure than what is currently recommended is better. But I looked at the data and I'm scratching my head.

A general picture of the trial: Participants were non-diabetic hypertensives aged 50 and older. About half (over 4,600) were randomized to therapy that would reduce their blood pressure to less than 140mm Hg. The other half had more intensive pharmacotherapy to get their bp to less than 120mm Hg. The former group averaged 2.8 medications per day, the latter 1.8 meds. Primary outcome was a composite of cardiovascular events including heart attack, stroke, and CV death.

Results: Here's where the rubber meets the road. And frankly the winner zipped past the finish line just a fraction of second earlier than its competitor. Media reported a 25% drop in cardiovascular events in the intensive therapy group. However, the sober truth behind the lurid reporting is that the absolute risk dropped from 2.19% to 1.65% (after 3 years of treatment). That's a measly one half percent. All-cause mortality dropped even lower--just over a third of a percent.

But given the number of hypertensive patients even in the US alone, such a small reduction could potentially prevent a huge number of CV events--even if the data shows that we'd need to give 185 patients an additional pill daily to save one patient from suffering a heart attack, heart failure, stroke, or some other CV event (after a few years of treatment).

But then the trial also discovered a few worms--big ones which should make doctors wary. The NEJM quick take doesn't provide the numbers, but it does tell us that there were more adverse events in the intensive therapy group, events such as syncope (loss of consciousness from hypotension) and kidney failure.

So you have greater benefits, on the one hand, but then greater risks for adverse events as well. So is it really beneficial for hypertensives to bring their bp down to less than 120? Perhaps it would eventually become a judgement call--a decision that doctor and patient will have to arrive at after taking into account the patient's lifestyle, other medical conditions, goals in life, risk aversion level, etc.

2016 USPSTF breast cancer screening recommendations

The latest recommendations are finally out.

I have a beef with its recommendation for the 50-74 age group: They base their decision on the fact that reviews of studies show a decreased breast cancer mortality in those screened. However, the task force clearly knows that screening does not reduce deaths from all causes. They say so right there in their statement: "None of the trials nor the combined meta-analysis demonstrated a difference in all-cause mortality with screening mammography."

What does this mean? Well, apparently screening programs do reduce the number of breast cancer deaths (within a specified time period, eg. per year) but then increases the deaths from other causes, thus nullifying the reduction in the breast cancer mortality. So some women will not die from from breast cancer while others get the short end of the stick and die from something else instead.

So why recommend screening when it does not affect death rates from all causes? Why not underscore this vital information, make certain women know about it, and then have them decide whether they want to go through a screening regimen to reduce their risk of dying from breast cancer but then increase their risk of dying from other causes?

"Science has taken a turn towards darkness"

The case against science is straightforward: much of the scientific literature, perhaps half, may simply be untrue. Afflicted by studies with small sample sizes, tiny effects, invalid exploratory analyses, and flagrant conflicts of interest, together with an obsession for pursuing fashionable trends of dubious importance, science has taken a turn towards darkness. 

 --Richard Horton, editor-in-chief of the Lancet 

Similar conflicts of interest and biases [as those in psychiatry] exist in virtually every field of medicine, particularly those that rely heavily on drugs or devices. It is simply no longer possible to believe much of the clinical research that is published, or to rely on the judgment of trusted physicians or authoritative medical guidelines. I take no pleasure in this conclusion, which I reached slowly and reluctantly over my two decades as an editor of The New England Journal of Medicine. 

--Marcia Angell, former editor-in-chief of the NEJM

Antidepressants are active placebos

[W]hen the level of blinding was high and it was difficult for the investigators, their staff and depressed patients to guess treatment assignment, the differences between these treatments, controls and placebo became quite small. [Kahn and Brown]

Antidepressants work. But they do so only because they elicit a large placebo effect. As has been shown time and again by randomized clinical trials the placebo control always nearly reaches the therapeutic rate of antidepressants. In other words, antidepressants are largely just expensive placebos.

However, that is not quite on the mark. Antidepressants are not just placebos; they are active placebos. Meaning, they produce a range of side effects. And unfortunately some of these are quite serious such as increased risk of suicide and harm to others (including murder), particularly among children, teens and young adults. Moreover, a number of antidepressants can become addictive in the sense that depression-like symptoms occur if the drug is abruptly stopped after having been taken for months. These are drug withdrawal symptoms not a relapse of depression.

The best advice, particularly for those with mild to moderate depression, is to keep away from antidepressants and go for non-drug therapies instead. Such therapies also trigger the placebo effect but don't have the adverse effects of pharmacological agents.

Oliver Sacks, 1933-2015

He went gentle into that good night
In old age he did not burn and rave at close of day
He did not rage against the dying of the light
He went gentle into that good night

So long, Dr. Sacks

From his article in the New York Times earlier this year:

I have been increasingly conscious, for the last 10 years or so, of deaths among my contemporaries. My generation is on the way out, and each death I have felt as an abruption, a tearing away of part of myself. There will be no one like us when we are gone, but then there is no one like anyone else, ever. When people die, they cannot be replaced. They leave holes that cannot be filled, for it is the fate — the genetic and neural fate — of every human being to be a unique individual, to find his own path, to live his own life, to die his own death. 

I cannot pretend I am without fear. But my predominant feeling is one of gratitude. I have loved and been loved; I have been given much and I have given something in return; I have read and traveled and thought and written. I have had an intercourse with the world, the special intercourse of writers and readers. 

Above all, I have been a sentient being, a thinking animal, on this beautiful planet, and that in itself has been an enormous privilege and adventure.

Keeping blood pressure among the elderly at a high enough level

Alan Cassels talks about the dangers of keeping blood pressure low among the elderly.

People who talk about prescribing in the elderly call it an 'evidence-free zone.' ... [B]lood pressure makes a very poignant example of the kind of care the elderly can often be subject to.... The problem is that trying to get blood pressure that low for someone who is 80 is almost totally irrational. Why? Because the physiology of old people is different and most blood pressure studies have specifically excluded people aged 80 and over. Those few studies that have focused on the elderly find something terribly surprising: the patients in the trials who had lower blood pressure had a higher risk of death.

This gets my goat. Because some doctors treat the elderly like they're middle aged and drown them in antihypertensives to keep their bp within the range appropriate for half century old individuals. Hence adverse effects can kick in. As in dizziness and light headedness in my mom's case. Seemingly unable to think out of the box, these doctors (hopefully in the minority) treat their now septua- and octogenarian patients as if they were still in their 50s. And worse, patients have been indoctrinated into believing there is an unquestionable Goldilocks zone for bp which is true for everyone and for all ages. And so they happily go along with their physicians' recommendations.

False positives, incidentalomas, overdiagnosis

"More testing leads to more false positives and incidental findings (abnormalities that don't pose a risk to your actual health). That leads to a higher probability of treatment. And treatment carries side effects." --Charles Ornstein

And from Dr. Gilbert Welch:

The more tests you do, and this is only the statistical process, the more likely one of them will be falsely abnormal. And the more times you do it, the more chance that something will be falsely abnormal.

The problem is you'll always be catching things out of what we would say is normal. This is anticipatory medicine at its worst, where you're really focused on what could be going wrong in the future and you're trying to pick up [a] signal.

The problem is there's so much noise — because the human body is a living organism. Variation is the very essence of life. People will start reacting to this data. I also think it's really important to label it what it is: data. To me it only becomes information to the extent that it accurately predicts something will happen in the future, and it only becomes useful knowledge — a higher level piece of information — if we can do something about it.

[http://www.npr.org/blogs/health/2015/04/06/397848621/tracking-your-own-health-data-too-closely-can-make-you-sick]

Breast cancer overdiagnosis due to screening mammography

Daniel Kopans says, "Overdiagnosis is a myth that has been created by a handful of individuals who provide no care for women with breast cancer."

And yet according to one of the latest studies the cost of overdiagnosis from screening mammography in the United States alone is $1.2 billion annually.

Really difficult to put much stock in what someone with vested interest in mammography says, specially when there are others (without conflicts of interest) producing evidence to the contrary.

[http://www.startribune.com/lifestyle/health/298805201.html]
[http://content.healthaffairs.org/content/34/4/576.abstract]

Web of corruption in clinical trials

Peter Wilmhurst shares his experience of the web of corruption involving industry, doctors, researchers/trialists in the following Evidence Live 2014 talk. Treatment efficacy and patient welfare were the least of their concerns.

Cholesterol Drug War

Watch the 2013 Australian Broadcasting Corp. documentary on statins.

The lone doctor interviewed in favor of statins almost sounds like a pharma shill. Makes one wonder whether he has conflicts of interest to declare.

Epidemic of diagnosis of thyroid cancer

Incidence of thyroid cancer has been going up. Steeply. But the mortality rate has been as flat as the Bonneville Salt Flats. Ergo, either we have an excellent treatment regimen for thyroid cancer or we have an epidemic of thyroid cancer diagnosis. It's the latter.

Currently, there is no way to confidently predict which incidentally detected thyroid nodule may be the precursor to a more aggressive process. Predictions such as these would require more accurate characterization of the biology of individual thyroid cancers than is currently possible. With time, we might prove our ability to confidently differentiate low-risk from high-risk thyroid cancers, but until that happens, routine screening for thyroid cancer by imaging billed as a “health checkup” should not be performed

[http://archotol.jamanetwork.com/article.aspx?articleID=2276788]

Dr. Gilbert Welch explains this lucidly in his cancer screening video (@11 min.)

Antibiotics-bacteria chart

Finally, someone made a quick guide

[http://wellingtonicu.com/Data/Antibiotic%20Overview.pdf]

Statins linked to diabetes

While the study is retrospective in nature, evidence is apparently mounting that there is a significant correlation between statin use and diabetes.

Quality of life

Longevity is not the be all. Being isn't just a matter of continuing to be alive and staving off death as much as we can. What's more crucial when the medical community and the patient and his/her family feel they're facing the final curtain is quality of life, or more to the point, the quality of remaining life. In the contest between mere quantity and marked quality, the latter surely must trump the former. Life extension makes sense only if the additional days, weeks, months that we can buy aren't spent in unremitting pain and suffering, in unending rushes to the ER, or in being incarcerated to the very end in a hospital with a welter of wires and tubes dangling off our face and body. Life is worth prolonging only if we are not consigned to living out the rest of our days in a hell on earth. We must rage against the dying of the light. And old age should burn and rave. But only if there is still a life worth living.

Science Babe on the Food Babe

Yvette d'Entremont exposes Vani Hari's breathtaking ignorance.

Reading Hari's site, it's rare to come across a single scientific fact. Between her egregious abuse of the word "toxin" anytime there's a chemical she can't pronounce and asserting that everyone who disagrees with her is a paid shill, it's hard to pinpoint her biggest sin.

Atul Gawande on overdiagnosis

In his New Yorker article Dr. Atul Gawande talks about--among other things--overdiagnosis:

More than a third of the population turns out to have these tiny cancers in their thyroid, but fewer than one in a hundred thousand people die from thyroid cancer a year. Only the rare microcarcinoma develops the capacity to behave like a dangerous, invasive cancer.

Trial discontinuation, non-publication and non-contactable investigators

One in five surgical randomised controlled trials are discontinued early, one in three completed trials remain unpublished, and investigators of unpublished studies are frequently not contactable. This represents a waste of research resources and raises ethical concerns regarding hidden clinical data and futile participation by patients with its attendant risks. To promote future efficiency and transparency, changes are proposed to research governance frameworks to overcome these concerns.

[http://www.bmj.com/content/349/bmj.g6870]

PSA test for prostate cancer screening does more harm than good

Some doctors are better than others. And some are pathetically behind the curve. Why did the doctor I visited order a PSA test given that 1. I'm asymptomatic and 2. PSA screening has been shown to do more harm than good?

We know that the sensitivity and specifities of screening tests are imperfect. We also know the prevalence of the diseases they're trying to detect tends to be low. Hence, screening tests have high false discovery rates (the ratio of false positives to total positives). We also know the perils of overdiagnosis and overtreatment--detecting and treating abnormalities/cancers that will never be the cause of death of the individual. Therefore the rationale for ordering some screening (as opposed to diagnostic) tests is dodgy at best.

[https://www.harding-center.mpg.de/en/health-information/facts-boxes/psa]

Prostate cancer screening and innumeracy

"Research has shown that numeracy among the American public is shockingly low." Wouldn't be surprised if "shocking" innumeracy isn't confined to the United States.

Many laypersons do not understand that a control group is needed in order to evaluate the effectiveness of a medical intervention or test. By attending primarily to cell A and by giving insufficient attention to cells C and D, many members of the general public will not comprehend a central basis for the task force’s negative opinion of the PSA test.

This insufficient attention to disconfirming information is the good old fallacy of confirmation bias.

Given a 4ng/ml cutoff, PSA screening has a laughable sensitivity of only 21%. And even with a specificity of 94%, the false discovery rate still comes out to a whopping 81% for a cancer prevalence of 6.3%. That just means that out of every 5 men who test positive, 4 were incorrectly tagged. Epic fail.

Now I read in some cancer website that 1 in 7 men will have prostate cancer. Let's round that up to 15%. If we take that as our base rate (prevalence), we obtain a false discovery rate of 61.8%. So out of every 5 we will still be erroneously labeling 3 as having cancer.

Now that's just the false positives--those who don't have cancer. What about the true positives--those who actually have some type of prostate cancer? PSA does not distinguish between aggressive cancers and those that progress very slowly. The latter need not be treated, will probably not cause discomfort or some disability in the patient's life, and will almost surely not be the cause of his death. But the fact that cancer has been discovered almost certainly will prod both patient and doctor to fiddle around with it further, calling for more tests and even (invasive) treatment of sorts.

[http://citrixweb.mpib-berlin.mpg.de/montez/upload/PaperOfTheMonth/arkes.gaissmaier.2012-1.pdf
]

Gawande's The Checklist Manifesto and reduction of surgical complications

Just finished Dr. Atul Gawande's The Checklist Manifesto: How to Get Things Right. It is so well written, moving and gripping that I would've gone through it in one sitting had the rest of life been kind enough not to butt in. In 2007 to 2008 a team of doctors and researchers, including Gawande, under the auspices of the World Health Organization performed a study that involved hospitals and surgical teams in eight developed and third world countries (USA, Canada, New Zealand, UK, India, Jordan, Philippines, Tanzania) to test the effectiveness of a simple 2-minute, 19-item surgical checklist the team had developed. In both his book and in a TED vid (starts at around 14:00) Gawande shares the incredible and almost unbelievable results they obtained: a drop in the number of deaths by 47% and in overall major complications by 36%.

Imagine being able to cut mortality rate in half! At very little cost and with no invasive procedures, drugs and side effects. Given how checklists have been effective in a number of areas including the airline and construction industries, it stands to reason that medicine could benefit from having checklists in place to make sure vital items/steps are not missed or incorrectly performed.

And now for the nitpick. First and quite clearly this was not a randomized, blinded clinical trial so certain biases may have affected the results. As Gawande himself pointed out, among other things, he was concerned the Hawthorne effect may have kicked in (but as he says the fact that observers were in place during the baseline data collection phase ought to have canceled out any effects resulting from that effect.) Secondly, and specifically with how Gawande presented the study findings, the double digit numbers can be misleading and can inflate the benefits of the intervention (the checklist). And this is because Gawande chose to impress us by providing the relative risk reduction and not the absolute numbers or percentages. For those figures I had to search for their published study. And so in their NEJM paper the results they obtained were summarized as follows:

The rate of death was 1.5% before the checklist was introduced and declined to 0.8% afterward (P=0.003). Inpatient complications occurred in 11.0% of patients at baseline and in 7.0% after introduction of the checklist (P = 0.001). 

Given the p values these results are statistically highly significant. Using the absolute risks above the absolute reduction in death is 1.5 - 0.8% = 0.7% and in overall complications ARR = 11% - 7% = 4%. In other words, 1 out of 143 inpatients was spared an untimely and needless death, and 1 in 25 spared major complications. These numbers I believe provide a much more realistic picture. Because death and complications are--fortunately--not that frequent (1.5% and 11%, respectively), quoting relative risk reductions has the tendency to mislead and to exaggerate the benefits (or risks).

Nonetheless, given that such a simple, inexpensive, apparently harm-free intervention does reduce major complications, particularly death, ought to be sufficient to spur the medical field to study checklists further, and implement, fine tune and improve the checklist that Gawande et al. have created.