More Smoke and Mirrors on Statins, Brought to You by Pfizer

An esteemed colleague called my attention to:
http://content.healthaffairs.org/content/31/10/2276.full
--in which a team of authors, who either work for Pfizer or who mostly have extensive financial relationships with the drug industry, explain to us that prescribing statin drugs is a huge economic plus for society. According to their calculations, prescribing statins aggressively even for people at low risk for cardiovascular disease costs the US each year about $305B and yields health benefits worth $1.25T. So naturally they recommend revising guidelines to recommend statins for more people and in even higher doses, and more vigorous use of pay-for-performance incentives for docs to get on the ball and prescribe more statins.

Sounds like a no-brainer, right?

Of course in this blog I've been harping on all the accumulated evidence that statins have been way overhyped and are probably of little use in all groups except those with already-diagnosed cardiovascular disease. So what's the deal?

It turns out that a careful reading of the article shows that Exhibit A for the huge success of statins, according to which the authors then calculated their economic benefits, was the CTT meta-analysis which I have previously alluded to: http://brodyhooked.blogspot.com/2012/05/statins-in-water-supply-continued-why.html

In that earlier post I took advantage of the expertise of David Newman to explain why the CTT analysis basically answered the wrong question--not, what happens if you put people in various risk categories on different doses of statins; but what happens if you prescribe statins and the result is that a patient's LDL level drops by a certain number of points. If you do an analysis the latter way, then statins appear to be marvelously useful, but as explained in the earlier post, that doesn't answer the doc's question about whether it's good to start the statin in the first place. If you answer the question in the former manner you get the more pessimistic numbers that show no real benefit except in the highest-risk groups.

Here's the other kicker in the more recent economic analysis, this amazingly bald statement near the begimnning of the article: "Importantly, we do not account for possible side effects in our social value calculations below." Come again? If statins make half the people who take them sicker than dogs, that doesn't count as a social cost--so your number-crunching simply assumes that statins are completely free of side effects?

The authors try to finesse this by noting that statins cause low levels of adverse reactions in many of the large-scale studies of efficacy--studies for the most part sponsored by the drug industry. This ignores the accumulating evidence of serious adverse reactions, even though most of them are not deadly, thank goodness. Consider for example a research letter by Golomb and colleagues (subscription required), noting from randomized trial data that as many as 4 in 10 patients might have worsening of fatigue and energy loss when taking statins; or other recent evidence raising the question of memory impairment as a consequence of statin use.

So what are we to conclude? First, this recent economic "analysis" is incomplete for omitting adverse reactions, and is probably deeply flawed by being based on a flawed meta-analysis of trial data that asks the wrong question. Second, this is how industry marketing works. First, get a study that's methodologically weak, but that contains the message your marketers wish to convey, out there in a prestigious journal (in the case of CTT, The Lancet). Second, keep churning out more and more articles conveying the same marketing message, referring back in each case to the first article, and hope that the journal's prestige will prevent any readers from questioning the methodology closely. Third, you can prove anything you wish in a cost-benefit analysis, just be sure to make the assumptions that tip the scale your way.

Golomb BA, Evans MA, Dimsdale JE, White HL. Effects of statins on energy and fatigue with exertion: results from a randomized controlled trial. Archives of Internal Medicine 172:1180-82, August 13/27, 2012.

The Price of Leukemia Drugs: 100 Doctors Protest

I generally try to avoid posting on the price of drugs, as I see that as less directly related to the ethical issues at the interface of medicine and the pharmaceutical industry. However, to the extent that physicians interpret their medical professionalism as requiring patient advocacy, and drug prices prevent patients' access to needed drugs, then the issue moves front and center. And when prominent physicians push back against the drug industry, that's also news.

So:
http://bloodjournal.hematologylibrary.org/content/early/2013/04/23/blood-2013-03-490003
--we have a statement in the journal Blood, the organ of the American Society of Hematology, signed by 100 prominent physicians from around the world who all treat leukemia, objecting to the price of newer drugs for that disease.

In HOOKED, I wanted to start the book with a couple of narratives about drugs, one showing the pharmaceutical industry as knight in shining armor, the other showing the dark underbelly of drug marketing--just to try to set a tone of even-handedness at the get-go. I selected the drug Gleevic as my Exhibit A for Pharma good behavior. In order to do that I had to soft-pedal one of the problems with that drug for chronic myelogenous leukemia (CML)--the way Novartis set its price, guaranteeing a very high profit margin and exceeding considerably (as it turned out) their investment in research. (One of the signatories to the new statement is Brian Druker, whom I discussd in HOOKED as an early advcate for the drug and who tried to push Novartis to do clinical trials in early days when the company was reluctant.)

Since Gleevic entered the market, a number of related compounds, all in the class of tyrosine kinase inhibitors, have come on line, and are priced even higher--in excess of $100,000 per year. (Gleevic came on the market in 2001 at a price of about $30,000 annually and has now risen to $92,000.) These drugs are the nearest thing to the proverbial magic bullet in cancer treatment--they are highly effective at suppressing cancer cells but cause very few side effects. When I wrote HOOKED, the long-term story of CML therapy with these drugs was unknown--would they keep working year after year? Could a patient stop taking them and be cured, or would the patient need routine maintenance, maybe for life? As things have worked out, as best as I can tell from the Blood paper, it's the drug industry's dream come true--the drugs keep working but the patients have to keep taking them forever. So those big bucks just keep rolling in--if the patients can afford to pay.

The 100 leukemia physicians object to these prices preventing many patients, especially in poorer nations, ever having access to these drugs, and they protest that there's no justification for the high prices based on the true costs of R&D.

The article begins by referring to the concept of the "just price." This, the authors explain, is based on "moral necessity" where "price must reflect worth." The cynic would wonder what planet these folks live on. Everyone knows that on this planet, prices reflect one thing and one thing only--what the market will bear, and morality be damned. If the drug industry actually started thinking like these physicians recommend, one shudders at the consequences.

Med Students Score Again with AMSA Scorecard

In the 6 years I've been doing this blog (hard to believe), we've seen a number of successes in the struggle to free medicine from inappropriate entanglements with commercial interests, as well as a number of areas where progress if any is very slow. One great success has been the adoption of stricter policies by medical schools and academic medical centers--and a huge stimulus for this change has been the American Medical Student Association's scorecard for conflict of interest policies. These scorecards were an incredibly shrewd political statement--nothing like telling the dean of a med school that their place got an F on a "report card" to get his or her attention.

The latest round of scorecards is out and continues to show progress--see:
http://postscript.communitycatalyst.org/?p=3297

Particularly interesting is an interview with an associate dean at a brand-new med school, noting that they were able to build a strong COI policy from the ground up as they began operations thanks to the guidelines provided by the AMSA scorecard. This highlights the importance of generational change. As faculty and students who remember the bad old days when drug reps roamed the halls of academic centers liberally dispensing "free" lunches and other goodies recede into the past, and a new generation comes along for whom avoiding COI is simply the norm, things change, and complaints that used to be voiced suddenly are heard no more.

Translational Research--What Does It Mean?

The occasion for these musings is Dr. Barney Carroll's post over at our friends, Health Care Renewal:
http://hcrenewal.blogspot.com/2013/04/walk-walk-for-some-time-jeremiad-theme.html

Dr. Carroll once again focuses our attention on Dr. Charles Nemeroff and his checkered career at Emory University, in this case getting a big grant that ended up producing nothing of note, in the name of "translational research." This allows Dr. Carroll to make some trenchent comments about the current state of research in psychiatry, such as: "Lost in the wailing [over academics' loss of research funding by drug companies] is a clear understanding that the defecting corporations are acting out of their own enlightened self interest. For 50 years, no fundamentally incisive innovations have occurred, so the defectors are telling the academics to get their act together in respect of better understanding disease mechanisms. Trouble is, too many academic clinical investigators have devolved into key opinion leaders promoting corporate marketing messages at the expense of generating original clinical science. Now they are squawking about being caught with their pants down."

A word, now, about the notion of "translational research," in the name of which this big grant to Emory from the National Institute for Mental Health was awarded, and then renewed, despite lack of scientific productivity (and with some concerns for conflicts of interest). Translational research, when the Feds began trumpeting this new paradigm several years ago, seemed to have two alternative meanings. The meaning that I respect and favor is that investigators in academe must be more concerned and informed about the entire process of research that takes new discoveries from the lab to the patient's bedside and eventually to widespread community applications. Translational research requires interdisciplinary teams of scientists and clinicians. From my vantage point at the outer reaches of a translational research effort, this has proven harder to do than most guessed. Scientists educated the old way are simply not trained to talk with other scientists outside their field, let alone clinicans seeing patients and people who work in community programs. Indeed, the major contributions a translational research center might make in the long run is creating a way to better train the next generation of scientists and research-clinicians.

But some of us worried all along that to some, at least, "translational" had a more sinister meaning--"get academic scientists in bed with industry early and often." What Dr. Carroll's post seems to me to illustrate most forcefully is that the idea that one could get a big grant, include both academic scientists and a big drug company in the project, add water and stir, and magically wonderful new drugs would appear out the other end to cure all our ills, is simply insane, and could have been known to be insane from the get-go.

As I explained in HOOKED, my own nonexpert opinion is that major new discoveries in drug treatment are for the most part some years away and cannot be produced according to anyone's industrial or marketing timeline. This is not because really smart people aren't busting their buns to try to discover new drugs. It is simply a reflection that we have probably picked all the low hanging fruit from past discoveries of basic disease mechanisms, and that before we can come up with generations of new, useful, and safe drugs, we need to make more basic discoveries about disease mechanisms. That sort of research is notoriously unpredictable. A solid translational research effort will focus appropriate resources on basic research into mechanisms, and then try to tie that research in a useful way to what we know about clinical and community applications. It won't shortchange basic research in the name of having a product to bring to market next week.

"The Emperor Wears a Thong"--More on Diabetes

I've referred many times to the myth that tight control of blood sugar levels in adult-type (type 2) diabetes confers any real patient benefit, despite the drumroll from advocacy groups and marketers to have patients checking their blood sugar with their monitors practically every 5 minutes. A very handy summary of the evidence we're here surveyed in a number of scattered posts can be found in:
http://onlinelibrary.wiley.com/doi/10.1111/j.1532-5415.2012.04057.x/abstract;jsessionid=EDB68E038FF876D039DFF928CE630DA1.d02t03

As the subtitle, "The Emperor Wears a Thong," suggests, the author is not willing just yet to say that the emperor of diabetes tight control wears no clothes at all--but I find it hard to read his article as really saying anything but this.

The article, by distinguished geriatrician Dr. Thomas Finucane from Johns Hopkins, focuses especially on the older patient--the group where the side effects of diabetes drugs are most likely to cause serious and even life-threatening problems. He reviews the various research studies that all fail to show any consistent reduction in important health outcomes when patients are subjected to efforts at lowering blood sugar aggressively.

Dr. Finucane pulls no punches as to where he thinks responsibility lies for our continued love affair with ever-lower blood sugar levels requiring ever-higher doses of drugs:

Worldwide, tremendous promotional efforts nourish the belief in “tight control,” and the market is huge. Every person with diabetes mellitus is a customer....

The timidity of performance-measurement initiatives, disease-focused charities, professional societies, and academics in confronting the discrepancy between the data and the public relations enterprise is a matter for serious consideration. A great deal of harm has been done to vulnerable elderly adults and others as a result of the public relations success with its echoing hue and cry. From a vendor's perspective, this is desirable.

In 1909, Sir William Osler said, “Far too large a section of the treatment of disease is today controlled by the big manufacturing pharmacists, who have enslaved us in a plausible pseudoscience.” His remark may be more accurate now than it was a century ago.

Hat tip to Primary Care Medical Abstracts for the reference.

Even the Poster Child Has Problems: Drugs for Hypertension

A perennial theme in this blog is the way American medicine and the general public have been oversold on drug treatment generally, and "prevention" in particular. Prevention is important because the numbers needed to treat, when you are trying to prevent later disease in a population that now has no symptoms, tend to be very high--you may for example need to treat hundreds of people for several years with a drug in order to prevent one death or heart attack or stroke. The possibility that many of those hundreds of people will suffer harm from the drugs, while only one benefits, has to be kept in mind.

A couple of fairly recent studies drive home this point on what many would consider the poster child for successful prevention--drug therapy for high blood pressure. (Subscriptions may be required for articles cited.)

An international team led by Diana Diao did a review for the very respectable Cochrane Collaboration of drug treatment for mild hypertension. Many of us need to be reminded that "mild" hypertension includes people with blood pressure as high as 159/99. In days when practice guidelines and pay-for-performance schedules make doctors feel like criminals for every patient who is not below 140/90, this is worth stating.

Dr. Diao and colleagues identified 4 randomized trials that were good enough to include in their review, including a total of nearly 9000 subjects. They could not find any evidence that drug treatment for hypertension in this range reduced total death rate, strokes, heart attacks, or other cardiovascular events, at least over a 4-5 year period of study. About 9% of all subjects had to be discontinued due to adverse drug reactions.

Now, if you have questions about the value of treating high blood pressure in regular folks, you should neverthess be convinced that it's extremely important in people with diabetes. The main treatment effect seen in successful trials of diabetes treatment (focusing now on the more common adult or Type 2 diabetes, and not speaking of Type 1 or juvenile diabletes that requires insulin) is the result of aggressive treatment of cardiac and vessel risk factors, of which high blood pressure is a major one. Generally it is thought that while you need to try to get blood pressure below 140 for non-diabetics, you need to shoot for 130 in diabetic patients.

So a Canadian group led by Dr. Kerry McBrien did another meta-analysis of randomized trials comparing standard vs. intensive treatment of blood pressure in diabetes-- trying to get blood pressure below 130 (intensive) as opposed to shooting for 140-160 (standard). They found 5 pertinent studies. Across these 5 studies they found no evidence for reduction in total death rate or heart attack in the more-intensive-treatment group. They did however find a slight decrease in the stroke risk--about a 1 percent decreased risk. They also found a lot more adverse drug reactions in the intensive-treatment group, including many that could have been fatal or that required hospitalization.

So what does all this mean? If we take people whose blood pressure is as high as 159/99, there's no good evidence that treating their blood pressure with drugs improves their long-term outcomes. Even in diabetics, the group who most needs good blood pressure control, working to get blood pressure super-low instead of just reasonably low provides hardly any added benefit, but imposes considerable added risk of harm.

So just how did we get brainwashed into thinking that it's medical negligence to allow a patient to go around with a blood pressure of 141/91--and that if need be, put that patient on 3 or 4 different drugs to control this terrible condition? Is it possible that drug industry marketing had anything to do with that? And if this is so for the poster child of successful prevention, hypertension, what does it say about so many other "preventive" regimens that rely on drug treatment?

Hat tip to Primary Care Medical Abstracts, as so often, for the citations.

Diao D, Wright JM, Cundiff DK, Gueyffier F. Pharmacotherapy for mild hypertension (review). Cochrane Database of Systemic Reviews, issue 8, 2012.

McBrien K, Rabi DM, Campbell N, et al. Intensie and standard blood pressure targets in patients with type 2 diabetes m,ellitus: systematioc review and meta-analysis.  Archives of Internal Medicine 172:1296-1303, 2012.