an exempler…

Posted on Sunday 24 November 2013

I’ve been otherwise occupied, and not so vigilant as usual about the things I usually follow. Catching up, there’s aplenty to report, but this particular issue has an emotional valence for me from a long time ago – at least forty years. It has to do with small differences in medicine:
by John D Abramson, Harriet G Rosenberg, and Nicholas Jewell, and James M Wright
British Medical Journal. 2013 347:f6123.

…From a pharmacoeconomic perspective, expanding generic statin therapy to millions of low risk patients would add drug costs of up to $1/day or more per person for no net health benefit. Furthermore, if cholesterol lowering becomes established in low risk people, the indications for new, more expensive cholesterol lowering drugs such as the ApoB Antisence drugs and PCSK9 inhibitors currently being tested in clinical trials will probably expand as well.

The dominance of industry sponsored clinical trials of cardiovascular prevention has produced a body of scientific evidence that largely limits clinicians’ interventions to drug therapy. Rather than being compelled by guidelines to prescribe statin therapy for people at low risk of cardiovascular disease, doctors would provide a far greater service by explaining the magnitude of the benefits and uncertainty about the harms of statins together with discussion of the epidemiological evidence showing that behavioural risk factors—including tobacco use, lack of physical exercise, and unhealthy diet—are responsible for 80% of cardiovascular disease:

What low risk patients need to know
  • Lifestyle factors—including lack of exercise, tobacco use, and unhealthy diet—account for 80% of cardiovascular disease
  • For people at low risk of cardiovascular disease [<10% risk over next five years], statins do not reduce the overall risk of death or serious illness
  • In order to prevent one heart attack or stroke, 140 low risk people [< 10% five year risk] must receive statins for five years
  • The side effects of statins—including muscle symptoms, increased risk of diabetes [especially in women], liver inflammation, cataracts, decreased energy, sexual dysfunction, and exertional fatigue—occur in about 20% of people treated with statins
by Fiona Godlee, editor BMJ
British Medical Journal. 2013 347:f6412

…There is a concern underlying their critique that will be familiar to BMJ readers. It is that all of the trials included in the CTT meta-analysis were funded by the manufacturer of the statin being studied. They list the various ways in which these trials might have exaggerated the benefits of statins and minimised the harms, and they summarise what low risk patients need to know. Top of the list is the benefit of lifestyle change, something that the dominance of industry sponsored clinical trials too often obscures.

None of this does much to bolster confidence in the published literature. Nor am I reassured by discussions at two recent meetings co-hosted by the European Federation of Pharmaceutical Industry Associations (EFPIA). Drug company AbbVie is suing the European Medicines Agency to stop summary reports of its clinical trials becoming publicly available [doi:10.1136/bmj.f1636]. AbbVie’s lawyer made clear that the company considers even the data on adverse events to be commercially confidential. Despite industry’s claims to be in favour of greater transparency, EFPIA and its American counterpart PhRMA are supporting Abbvie. The BMJ and BMA have joined forces to intervene on behalf of the EMA [doi:10.1136/bmj.f4728].

As for a way forward, I can’t improve on the list of solutions proposed by Richard Lehman when emailing out his journal review blog this week []: “All phase 3 trials to be designed and conducted independently of manufacturers, using the best available comparator. Research priorities to be determined by patients (James Lind Alliance). Value-based pricing. All data available from all trials, with meta-data: IPD [individual patient data] level for qualified independent centres. Big increase in comparative effectiveness research, much more research into non-pharmacological treatments.”
After four whirlwind years of clinical training in a big-city [desparate illness] charity hospital and doing a research fellowship along with clinical responsibilities, I found myself in 1971 working regular hours in a military hospital seeing patients from a more or less healthy population. It was the era when guidelines were coming into vogue – when do you treat blood pressure? how tightly do you control blood sugar? what’s the upper limit of cholesterol? weight? The ‘executive physical’ had become popular with stress tests, pap smears, and sigmoidoscopies. Preventive medicine had moved from the world of immunizations to the "healthy lifestyle" doctoring of the present. I was a young contientious doctor, doing the right things. And I didn’t much like that part of it. The blood pressure medications I gave to people with minimum elevations had a heavy downside. The burden of tight diabetic control was pretty limiting. Trying to get overweight Air Force Sergeants to slim down was something of a lesson in futility. I didn’t know how to do some of the calculations back then, but I had a feeling that we were in the range of some very small differences [and in many cases, we were]. I just didn’t feel genuine when I passed on many of the guidelines I was given. And over time, it has gotten worse. And I didn’t enjoying focusing on the numbers so much. I think that was part of my decision to change specialties. The patient’s lives seemed so much more relevant than decremental changes in their diastolic blood pressure.

A Vignette: A friend down the road had been having a lot of muscle pain and stiffness and had been "sentenced" to Yoga Classes by his wife [which massively increased his symptoms]. On another day, he was talking about medication costs. He mentioned he’s taking a Statin that’s not yet generic. It costs a "mint," but his doctor says that it’s the "best one." Last night they were over and he mentioned he’d gotten back his most recent cholesterol count and said the number. His LDL [bad cholesterol] was "way down" [from normal to even more normal].

The bottom line
Our calculations using data presented in the 2012 CTT patient level meta-analysis show that statin therapy prevents one serious cardiovascular event per 140 low risk people (five year risk <10%) treated for five years. Statin therapy in low risk people does not reduce all cause mortality or serious illness and has about an 18% risk of causing side effects that range from minor and reversible to serious and irreversible. Broadening the recommendations in cholesterol lowering guidelines to include statin therapy for low risk individuals will unnecessarily increase the incidence of adverse effects without providing overall health benefit…from Abramson et al [above]

After looking at all these psychoactive drug trials, I am learning more precise ways of thinking about all of this. For a drug to have a demonstrable statistical superiority over sugar is certainly of interest, but hardly justifies it being turned into a multi·billion dollar phenome – which is exactly what has happened repeatedly. There’s something else that can be said about such comparisons, the strength of effect being one. Just because a drug has antidepressant properties in a large cohort, doesn’t mean it will be a clinically meaningful effect in many depressed people. And those numbers are frequently omitted from articles – things like odds ratio, number needed to treat [NNT], effect size, etc. And then there are adverse effects [side effects] and serious adverse effects [SAEs]. They can be quantified as things like risk ratio, relative risk, or number needed to harm [NNT]. In the end, all of these things can be combined into a risk·benefit ratio, and while there are some ways to quantitate this, it’s usually discussed subjectively as in these articles.

I grew into doctor·hood when such things were more narrative than  mathematical. Digitalis could be a life·saver or a poison, and I could say that in words to patients and explain why it was both. I thought of drugs categorically, as powerful or weak, as safe or dangerous, with not much in between on either axis. I thought of classes of drugs [the penicillins] more in terms of their similarities than their differences. Now, in the Age of Clinical Trials, we are bombarded with articles that are preoccuppied with small effects and small differences among members of a similar class. One frequently sees patients who have tried every known SSRI without success, but come seeking another new one. Rather than concluding the obvious, no chemical help in sight and likely there’s something wrong in their life. They think they just haven’t tried the right antidepressant [after all, they are anti·depressants].

So back to the Statins, this is a multi·billion dollar phenome extra·ordinaire, and in large measure is as big a much·ado·about·nothing as it was in 1971 when I found myself balking at all the guidelines that kept coming. To me, Statins are for high risk patients, side effects or not. The rest of us should drive carefully, and stick to the basics ["Lifestyle factors—including lack of exercise, tobacco use, and unhealthy diet—account for 80% of cardiovascular disease"]. Dr. David Healy’s book, Pharmageddon, makes this point more eloquently than I, but, in my words, we have become a culture of small differences – differences that don’t really matter [and they even fudge on that eg Paxil Study 329]. And the Pharmaceutical Industry and the proliferation of Clinical Trials have had a big part in making us that way – by design. 

Back in 1971, I felt guilty about balking at following those many guidelines in my clinical work – in fact, too guilty not to do it. But it wasn’t how I wanted to spend my life. And back then was nothing compared to today. I don’t feel guilty anymore. The prescription of small differences medication and the doing of low yield medical tests accounts for a beyond sizable fraction of our overall medical cost burden, and this Statin escalation is a negative exempler of exactly why. At least that’s what I think. The good news is that the current focus on honest Clinical Trial reporting is a positive step towards doing something about it…
    November 24, 2013 | 1:15 PM

    In the lifestyle category, I’d like to see adequate sleep on the list.

    Some people keep looking for the antidepressant that works because they’ve been convinced that their brain is faulty. That’s not a contribution to the public ethos to be proud of and it can be lain at the feet of the corrupt bond between psychiatry and drug companies.

    Ben Goldacre addresses statins and the corruption:

    November 24, 2013 | 1:41 PM
    November 24, 2013 | 3:41 PM

    That’s interesting, Annonymous, though it’s being treated as an adjunct to antidepressants.

    Since the pain has intensified with my MS, I have had to sleep in two shifts. It worried me— having my only psychotic episode with the only extended sleep deprivation I’ve ever experienced— until I read this, which reminded me of the story of the woman who stopped struggling with the voices she heard after she read a book about a theory about how the ancient Greeks thought.

    Steve Lucas
    November 24, 2013 | 4:27 PM

    For the last 10 years I have been bombarded with doctors wanting to medicate me due to some theoretical guideline. The reality is that in modern practices if you do not agree, or ask for evidence, you do not have a doctor.

    The ultimate irony of this was played out over a year ago as I was asked to take my wife’s 100 year old uncle in for a PSA test in January. January in our part of the country is filled with ice and snow and he was not mobile. Additionally he made regular visit to the hospital for treatments, a hospital that was on the same campus as the doctor’s office.

    I was upset at the possibility of injury and made my feeling known. My wife’s aunt discussed this with the doctor and the outcome was the doctor could not treat the uncle, even though he had been his doctor for many years, unless he made those 90 day office visits and submitted to some type of test.

    This ended that relationship and highlighted how guidelines, no matter how poorly designed, would be followed by some doctors even at the expense of possible physical harm to the patient.

    Steve Lucas

    November 24, 2013 | 5:38 PM


    Appreciate your frustration. My husband has been T1 diabetic for 56 years. He has managed to survive DESPITE the “latest, greatest, unpredictable, labile synthetic insulins that supplanted all natural products.” As a T1, of course, he requires insulin, delivery system (syringes or pump) and monitoring supplies. Now that he is “in the system” because he has Medicare (as well as private insurance), he MUST see his endocrinologist every 90 days . . . or no insulin, no supplies, no test strips! Is the paradigm to (1) judge/quantify compliance; (2) keep the money stream pouring into the medical industry; (3) educate; (4) use the very real threat of death to compel compliance?

    He, too, has been fired for asking questions and wanting to participate in his healthcare. But now, forced compliance does, indeed, rankle.

    [Another story: several years ago, trying to locate a new primary care doc, he had not completed all necessary lab work before initial consultation. After a friendly visit with the MD, hubby asked for a prescription (needed for insurance reimbursement) for his syringes and test strips. The reply: “I won’t write a prescription until all your lab work is completed and in my hands.” But, he shook hands with hubby, as he prepared to exit, and offered him two sample packs (gift of a previous drug reps of Lexapro . . . because diabetes IS depressing! Nowhere in the interview was depression or anxiety discussed. Go figure!]

    November 24, 2013 | 5:51 PM

    Rule of thumb: Resist taking any drug that’s advertised on television.

    When the new statin guidelines came out, I was on tenterhooks for the other shoe to drop — the revelation of drug company influence. Any day now!!

    November 24, 2013 | 8:17 PM

    Wow, Steve, Melody, that’s upsetting. The V.A. is very serious about vets being part of their health care team. Pushing veterans around doesn’t work well on the interpersonal level. Even in the psyche ward it’s understood that we can refuse any meds.

    We need to start paying for doctors’ education again so that we get people who really want to be healers in the healthcare system, not smug conformists who just want to make a lot of money.

    November 24, 2013 | 10:04 PM

    I wrote about this a few days ago per what I read from, and same agenda as with psych meds. Greed and lust don’t discriminate from specialty to specialty.

    November 24, 2013 | 10:15 PM

    I heard Steven Nissan on the radio awhile back pushing statins, and venting his frustration with all this squawking over side effects. Yes they can be unpleasant, he was saying in effect, but it’s not too much to put up with for a drug that is saving your life!

    The BMJ article above gives the lie to that. And it’s all the more ironic that the “minor” side effects discussed (which are not so minor for many people) all have the effect of making it much, much harder for people to be physically active. Which of course could go many times further than the best statin in terms of actually saving people from premature death by heart attack! It reminds me of the old story about killing the healthy chicken to make chicken soup for the sick chicken …

    There was a wonderful story on by a thoughtful uppity patient, a woman in her mid-sixties, about the uproar she faced in her doctor’s office for daring to question one “preventive” prescription. The drug in question was Fosamax for osteoporosis, not statins, but the idea was the same. She christened the problem “Iatroporosis” or Fragile Doctor Syndrome:

    Nick Stuart
    November 25, 2013 | 2:08 AM

    Wiley – ‘how ancient greeks thought’ is from a book by Julian Jaynes – ‘the bicameral mind’. I have read it and found it interesting. He speculated that consciousness was a recent human development and that ancient people attributed their thoughts to voices from the Gods… I think. I dunno what to make of it though.

    November 25, 2013 | 8:03 AM

    It’s that whole “evidence based medicine” thing that caused all this.
    Pharma came up with a way to show treatments ‘worked’ without ever having to explain ‘how’ they worked. Then it became easier to fudge the data a little to increase sales. Then guidelines were made out of the resulting noise.

    Statins are every effective in lowing LDL cholesterol. Does that mean LDL cholesterol is even involved in cardiovascular disease? nope! As long as there is Empirical evidence to support the use of statins in people thought to be at risk for cardiovascular disease, then evidence can suggest statins are safe and effective in otherwise healthy people.

    Pharma can’t make long term investments in research to find the cause of human diseases, they can only make short term investments in ghost writing and tweaking already existing drugs to renew the patent. We live in the age of ’empirical medicine’.

    Someone at MIT wrote an essay on why statins don’t work.

    November 25, 2013 | 11:50 AM

    We “exceptional Americans” scream about our rugged individualism; we HATE socialized medicine. Several years ago, when the statin debate was heating up, and the “numbers needed to treat” was presented, I thought about the economics—the math—if you will. I never chased down the actual costs, but as the debate has now come back to the forefront, I checked out the price of a representative statin: Lipitor costs approximately $105/month; the generic form about $31/month.

    Consider that 140 people need to take a statin every day for 5 years for a single person to avoid a heart attack.
    140 x 365 x 5 x $1 = $255,500 (generic treatment)
    140 x 365 x 5 x $3 = $766,500 (branded: Lipitor)

    Individually, the math is this:
    1 x 365 x 5 x $1 = $1825 (generic treatment)
    1 x 365 x 5 x $3 = $5475 (branded: Lipitor)

    Now whether your drugs are paid for out-of-pocket or via insurance, the drug industry collects (low end) $255,500 to prevent a single heart attack. The fact that a heart attack has been avoided is great news for the single individual who has contributed $1825 to the collective NNT pot and avoided a heart attack. The other 139 have shelled out $253,675; they can pat themselves on the back for contributing to the welfare of ‘lucky heart attack avoider’ or recognize they have enriched BigPharma/BigMedicine while receiving no benefit. Using fear, guidelines, best-medicine protocol, one lucky individual has been subsidized by his fellow fear-induced medical consumers (patients) to the tune of $253,675. Hidden well beneath the radar, we see socialized medicine—privatize the profits, socialize the costs.

    (The math, on the high end, is even more appalling. The collective cost is $766,500 compared to the individual’s cost of $5475.)

    November 26, 2013 | 12:08 PM

    As said above by Melody:

    “Hidden well beneath the radar, we see socialized medicine—privatize the profits, socialize the costs.”

    One of the primary objective of Obamacare. When you see/hear who is the most voracious and insistent to tell us to go along with this intrusion into care, pay attention to the agenda, someone who is focused on profit, oh, and as an extra perk, dump the reponsibilities and consequences on others.

    Just like a business model should, eh?

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