One more post about cholesterol and I promise to lay off for a while.
Sharon Begley has written a great article for the Saturday Evening Post:
http://www.saturdayeveningpost.com/2012/04/24/wellness/cholesterol-conundrum.html
--reviewing the data showing the lack of benefit when statins are taken for primary prevention of cardiovascular disease, and especially going into the "number needed to treat" as a helpful statistic. Along the way she reviews the various adverse reactions associated with statins--diabetes, memory loss as well as muscle aches--and adds a recent study suggesting that if you take a statin and then exercise, your body's ability to repair muscle is reduced. (A wonderful way to prevent heart disease--make it harder to exercise.)
The article says so many good things that it seems petty to pick out one problem, but I was disappointed that Begley (apparently to try to make clear that she was not simply bashing statins for bashing's sake) gave the drugs credit for the marked decrease in deaths from heart disease over the last 3 decades in the US. No one I know of says that drop was due to statins and most believe it primarily related to lifestyle changes and maybe a bit related to better outcomes in the acute care of heart attacks.
Now, you might wonder, if all this is so, then how come the drug industry has been able to convince us to get so crazy about measuing everyone's cholesterol (even kids) and then precribing statins at the first hint of a high measurement? (Begley starts off with the very sensible observation, that if what we know about statins and primary prevention is indeed true, then most of the justification for doing screening cholesterol measurements goes out the window.) The possible answer to that question is contained in a recent article that addresses the "cholesterol myth." While the article itself tends to go overboard in recommending somewhat extreme nutritional approaches, the core message is worth making note of.
Dr. Duncan Adams of New Zealand recently wrote about the "Great Cholesterol Myth":
http://qjmed.oxfordjournals.org/content/104/10/867.long
The way Dr. Adams tells the story, Brown and Goldstein won the Nobel Prize for their discovery about the relationship between high cholesterol and heart disease. They were studying a very special population of patients--those with the gene for familial hypercholesterolemia, whose cholesterol levels are sky-high and who often develop premature heart attacks and vessel disease. Brown and Goldstein assumed that what they were seeing was cause and effect-- high cholesterol levels in the bloodstream cause the vessels to have defects. Dr. Adams marshals arguments that they had it backwards. What if the basic defect in the vessel disease seen in this select group of patients is super-brittle vessel walls? What if cholesterol makes vessel walls flexible? (After all, cholesterol is an essential chemical and we'd die if we had none of it in our bodies.) What if the genes these patients inherited make their vessel walls unable to absorb cholesterol, so they become brittle, and the unabsorbed cholesterol then floats around in the bloodstream?
Dr. Adams' theory shows how by studying a very select group, and then generalizing to the entire population, we could have ended up with the wrong idea about cholesterol as a cause for cardiovascular disease. (Begley explains why it turns out that cholesterol levels by themselves are a very weak predictor of heart attack risk.) Going from what's true of a person with a total cholesterol level of 500, and assuming the same thing is true for a person with a cholesterol of 201, is exactly how drug company marketing prospers.
Can we know for sure that Dr. Adams' hypothesis is correct and that the "majority" view of cholesterol is wrong? Hardly. But it's worth knowing that out there is a potential, logical explanation that could show why we're quite confused in our thinking of how to prevent heart disease. (Hat tip to Jerry Hoffman and Rick Bukata for pointing out the Adams paper.)
Friday, May 25, 2012
Wednesday, May 23, 2012
Statins in the Water Supply, Continued--Why the New Meta-Analysis Is Unreliable
In the immediately previous post, I said that I expected more commentary to appear on the CTT meta-analysis of statins for low-risk patients recently published in Lancet. In this post I will 1) report on one of those commentaries and 2) fill in what I failed to say in the previous post, which is why this whole issue is relevant here.
First, commentary, by Dr. David Newman of Mt. Sinai in New York, and author of the excellent book, Hippocrates' Shadow: http://smartem.org/content/data-drugs-and-deception-true-story
Dr. Newman asks why the CTT meta-analysis, which said that low-risk patients benefit from statin therapy, is so much at odds with previous reviews, conducted by reputable groups, whoch all agreed they wouldn't. He decided that it's because the older reviews answer one question and the CTT meta-analysis, another.
The old reviews, in his (and my) opinion, answer the real question: if patients are put on statins, will they benefit in terms of lower rates of heart/vessel disease and/or lower overall mortality? The answer is that right now there's no proof of that for lower-risk individuals without known heart or vessel disease.
The reason that the CTT folks got as different answer is because they asked a different question: if you go on statins, and if the result of going on statins is that your cholesterol drops by a certain amount, will you have less heart/vessel disease and lower overall mortality? They found that the answer is yes, and apparently Dr. Newman thinks they crunched their numbers reliably and so this is probably a true result.
Now, suppose I'm a family doc and Mr. Jones, a 50-year-old man with apparent low risk for cardiac disease, comes for his annual visit, and I have to decide whether to put him on a statin. The older reviews address my decision, showing that if all I know is what I know now, then I cannot predict reliably that Mr. Jones would benefit.
The CTT analysis is irrelevant. Maybe if I put Mr. Jones on a statin drug, then he'll drop his LDL (bad) cholesterol by a certain number of points, or maybe he won't. There could be many reasons why he won't--maybe his body works differently, or maybe he forgets to take his medications, or who knows what. Since I cannot guess how he'd respond to the statin, the new analysis really provides me with no useful information. The old studies provide useful information, suggesting that I might have a talk with Mr. Jones about his options, but certainly not specifically recommend a statin drug.
Put another way, the CTT analysis shows how one particular subpopulation of people placed on statins respond, and that for whatever reason--because of the statin, or for some other reason--they seem to do well. But the overall population (low-risk patients without existing disease) is not addressed.
Dr. Newman notes that given this highly selective subpopulation that they looked at, the CTT folks have no grounds to recommend what they did, which is that guidelines should be revised massively to increase the number of patients for whom statins are recommended. The CTT folks (I'd add) were also disingenuous to the extent of their not openly addressing how and why their study came to such different conclusions from the earlier meta-analyses, coyly suggesting it was because they are so much smarter and the old analyses were plain wrong.
OK, so now why am I once again ragging about cholesterol and statins, on a blog that's supposed to be about the ethics of the medicine/drug industry interface? I cannot find clear evidence that the CTT group is in the pay of the drug industry; but they are basically acting as if they were. They are illegitimately recommending that a vast number of new patients should be prescribed statins. They are doing so based on an incorrect analysis, in a way that would probably not be obvious to the average reader, but as Dr. Newman shows is quite evident to the expert who understands data analysis. The Lancet is aiding and abetting this distortion of the data, and by appending an enthusiastic commentary, is even tooting the horn louder in favor of prescribing more drugs. All in all, one more sorry illustration of how the medical literature all too often serves drug industry revenues rather than patient health.
First, commentary, by Dr. David Newman of Mt. Sinai in New York, and author of the excellent book, Hippocrates' Shadow: http://smartem.org/content/data-drugs-and-deception-true-story
Dr. Newman asks why the CTT meta-analysis, which said that low-risk patients benefit from statin therapy, is so much at odds with previous reviews, conducted by reputable groups, whoch all agreed they wouldn't. He decided that it's because the older reviews answer one question and the CTT meta-analysis, another.
The old reviews, in his (and my) opinion, answer the real question: if patients are put on statins, will they benefit in terms of lower rates of heart/vessel disease and/or lower overall mortality? The answer is that right now there's no proof of that for lower-risk individuals without known heart or vessel disease.
The reason that the CTT folks got as different answer is because they asked a different question: if you go on statins, and if the result of going on statins is that your cholesterol drops by a certain amount, will you have less heart/vessel disease and lower overall mortality? They found that the answer is yes, and apparently Dr. Newman thinks they crunched their numbers reliably and so this is probably a true result.
Now, suppose I'm a family doc and Mr. Jones, a 50-year-old man with apparent low risk for cardiac disease, comes for his annual visit, and I have to decide whether to put him on a statin. The older reviews address my decision, showing that if all I know is what I know now, then I cannot predict reliably that Mr. Jones would benefit.
The CTT analysis is irrelevant. Maybe if I put Mr. Jones on a statin drug, then he'll drop his LDL (bad) cholesterol by a certain number of points, or maybe he won't. There could be many reasons why he won't--maybe his body works differently, or maybe he forgets to take his medications, or who knows what. Since I cannot guess how he'd respond to the statin, the new analysis really provides me with no useful information. The old studies provide useful information, suggesting that I might have a talk with Mr. Jones about his options, but certainly not specifically recommend a statin drug.
Put another way, the CTT analysis shows how one particular subpopulation of people placed on statins respond, and that for whatever reason--because of the statin, or for some other reason--they seem to do well. But the overall population (low-risk patients without existing disease) is not addressed.
Dr. Newman notes that given this highly selective subpopulation that they looked at, the CTT folks have no grounds to recommend what they did, which is that guidelines should be revised massively to increase the number of patients for whom statins are recommended. The CTT folks (I'd add) were also disingenuous to the extent of their not openly addressing how and why their study came to such different conclusions from the earlier meta-analyses, coyly suggesting it was because they are so much smarter and the old analyses were plain wrong.
OK, so now why am I once again ragging about cholesterol and statins, on a blog that's supposed to be about the ethics of the medicine/drug industry interface? I cannot find clear evidence that the CTT group is in the pay of the drug industry; but they are basically acting as if they were. They are illegitimately recommending that a vast number of new patients should be prescribed statins. They are doing so based on an incorrect analysis, in a way that would probably not be obvious to the average reader, but as Dr. Newman shows is quite evident to the expert who understands data analysis. The Lancet is aiding and abetting this distortion of the data, and by appending an enthusiastic commentary, is even tooting the horn louder in favor of prescribing more drugs. All in all, one more sorry illustration of how the medical literature all too often serves drug industry revenues rather than patient health.
Monday, May 21, 2012
Back to Statins in the Water Supply--But On What Basis?
In the beginning was the polypill. This hypothetical product was first proposed by Wald and Law in 2003, based on the idea that with a general population at fairly high risk for heart disease, it made sense simply to put everyone above a certain age on a combination pill containing a statin for cholesterol, aspirin, and one or more drugs for blood pressure. A recent review by Katherine M. Carey, PharmD and colleagues reviewed a number of studies that tried to assess the vaolue and safety of one or another form of polypill and concluded that at best the results would be modest (subscription may be required):
http://www.theannals.com/content/46/5/688.long
Well, now says The Lancet, forget the polypill. Just put everyone above age 50 on a statin:
http://www.thelancet.com/journals/lancet/article/PIIS0140-6736(12)60694-1/fulltext
This advice is based on a recently-published-on-line meta-analysis by the Cholesterol Clinical Trialists (subscription required). Their study reviewed a total of 27 clinical trials of statins as primary prevention (that is, for people without known heart or blood vessel disease). They concluded that on combining all these trials, there was a clear advantage to using statins for primary prevention, and that the more they lowered your LDL ("bad") cholesterol, the better they were as a preventive.
To regular readers of this blog, such a study would require some explanation, because it contradicts evidence about statins and primary prevention that has by now been fairly well established, even if little understood by many physicians as well as the general public. See for example:
http://brodyhooked.blogspot.com/2009/07/more-on-statins-new-bmj-meta-analysis.html
--which discusses the low level of evidence that statins are any good for primary prevention, as well as raising questions about whether they do whatever good they do by means of lowering cholesterol.
I have been privy to some e-mail discussions among statin and evidence-based-medicine experts, and I believe that several are planning to write letters and commentaries disputing the conclusions of the new Lancet meta-analysis. I am not at liberty yet to share the details of their reasoning. However, I can point to one press response to the Lancet statement about putting everyone on a statin:
http://www.scientificamerican.com/article.cfm?id=statins-should-healthy-adults-over-50-take-them
Melinda Wenner Moyer, writing for Scientific American, interviewed several critics and pointed out a few of the problems with the CTT meta-analysis. The biggest flaw pojinted out by the critics she quotes is that while the CTT study pupports to demonstrate that statins are good for primary prevention, fully 60 percent of the study participants in the 27 pooled clinical trials had existing heart or vessel disease. To extrapolate from that population to the "low risk" patient identified in the title of the CTT study hardly seems kosher. The othet major criticism is that almost surely, the CTT trial vastly underestimates the frequency of averse reactions to statin drugs--in part, perhaps, because at least some of the clinical trials were designed specifically to exclude patients who had those adverse reactions, again a not-very-kosher study design.
I believe that as the weeks pass there will be even more serious criticisms lodged against the CTT study, so stay tuned.
Wald NJ, Law MR. A strategy to reduce cardiovascular disease by more than 80%. BMJ 326:1419-24, 2003.
Cholesterol Clinical Trialists' (CTT) Collaborators. The effects of lowering LDL cholesterol with statin therapy in people at low risk of vascular disease: meta-analysis of individual data from 27 randomised trials. Lancet doi:10.1016/S0140-6736(12)60367-5, published on line May 17, 2012.
http://www.theannals.com/content/46/5/688.long
Well, now says The Lancet, forget the polypill. Just put everyone above age 50 on a statin:
http://www.thelancet.com/journals/lancet/article/PIIS0140-6736(12)60694-1/fulltext
This advice is based on a recently-published-on-line meta-analysis by the Cholesterol Clinical Trialists (subscription required). Their study reviewed a total of 27 clinical trials of statins as primary prevention (that is, for people without known heart or blood vessel disease). They concluded that on combining all these trials, there was a clear advantage to using statins for primary prevention, and that the more they lowered your LDL ("bad") cholesterol, the better they were as a preventive.
To regular readers of this blog, such a study would require some explanation, because it contradicts evidence about statins and primary prevention that has by now been fairly well established, even if little understood by many physicians as well as the general public. See for example:
http://brodyhooked.blogspot.com/2009/07/more-on-statins-new-bmj-meta-analysis.html
--which discusses the low level of evidence that statins are any good for primary prevention, as well as raising questions about whether they do whatever good they do by means of lowering cholesterol.
I have been privy to some e-mail discussions among statin and evidence-based-medicine experts, and I believe that several are planning to write letters and commentaries disputing the conclusions of the new Lancet meta-analysis. I am not at liberty yet to share the details of their reasoning. However, I can point to one press response to the Lancet statement about putting everyone on a statin:
http://www.scientificamerican.com/article.cfm?id=statins-should-healthy-adults-over-50-take-them
Melinda Wenner Moyer, writing for Scientific American, interviewed several critics and pointed out a few of the problems with the CTT meta-analysis. The biggest flaw pojinted out by the critics she quotes is that while the CTT study pupports to demonstrate that statins are good for primary prevention, fully 60 percent of the study participants in the 27 pooled clinical trials had existing heart or vessel disease. To extrapolate from that population to the "low risk" patient identified in the title of the CTT study hardly seems kosher. The othet major criticism is that almost surely, the CTT trial vastly underestimates the frequency of averse reactions to statin drugs--in part, perhaps, because at least some of the clinical trials were designed specifically to exclude patients who had those adverse reactions, again a not-very-kosher study design.
I believe that as the weeks pass there will be even more serious criticisms lodged against the CTT study, so stay tuned.
Wald NJ, Law MR. A strategy to reduce cardiovascular disease by more than 80%. BMJ 326:1419-24, 2003.
Cholesterol Clinical Trialists' (CTT) Collaborators. The effects of lowering LDL cholesterol with statin therapy in people at low risk of vascular disease: meta-analysis of individual data from 27 randomised trials. Lancet doi:10.1016/S0140-6736(12)60367-5, published on line May 17, 2012.
Grief: You'd Better Suck It Up After Day 13
I have blogged previously about the American Psychiatric Association's controversial revision of its Diagnostic and Statistical Manual, the promised DSM-V--most recently:
http://brodyhooked.blogspot.com/2009/07/more-on-psychiatrys-dsm-v-mess.html
Critics have charged with what appears to be good reasons that the APA has launched an effort to reclassify many states that have previously been viewed as normal into mental illnesses, with no base in the scientific evidence, but with vast opportunities for Pharma to get wealthy selling psychoactive drugs for all these newly "discovered" diseases.
To primary care physicians like me, one of the most egregious reclassifications rumored to be included in the new DSM-V is grief. We have long been taught that while depression is a disease, grief is normal. Treating grief with antidepressants at best does not help and at worst simply postpones the normal healing process. Social support and psychotherapy is almost always the right treatment for grief, except in the few cases of abnormally prolonged or intense grief which have to be addressed as a special set of cases. But in any event, after loss of someone very close, something in the range of 9 to 15 months would be seen as a normal grief reaction.
Dr. Richard A. Friedman of Weill Cornell medical college in New York, writing in last week's New England Journal:
http://www.nejm.org/doi/full/10.1056/NEJMp1201794
--contrasts this standard wisdom about grief, which was how the existing DSM-IV categorizes the condition, with that of the working groups designing the new DSM-V. They intend to reclassify grief as a depressive disorder and suggest that after 2 weeks of mild depressive symoptoms, a bereaved person has crossed the line over into depression and should be treated as such. Dr. Friedman notes that there are zero scientific data to support this reclassification.
I have not been able to track down a source for this rumor, but I have heard murmurings that if the APA proceeds to issue the new DSM-V (apparently scheduled for next year) with this reclassification, some of the primary care physician organizations, including my own American Academy of Family Physicians, might vote formally to dissociate their members from DSM. This would be an unprecedented move as up till now, starting at least with DSM-III, all medical specialties have been willing to accept as gospel the disease classification proposed by the APA-- which by the way makes a ton of money from selling DSM as its proprietary product. But it is precisely due to the APA treating the DSM as its own private property and cash cow--along with the too-friendly association of leaders in psychiatry with the drug industry over many years--that has led to the present mess.
http://brodyhooked.blogspot.com/2009/07/more-on-psychiatrys-dsm-v-mess.html
Critics have charged with what appears to be good reasons that the APA has launched an effort to reclassify many states that have previously been viewed as normal into mental illnesses, with no base in the scientific evidence, but with vast opportunities for Pharma to get wealthy selling psychoactive drugs for all these newly "discovered" diseases.
To primary care physicians like me, one of the most egregious reclassifications rumored to be included in the new DSM-V is grief. We have long been taught that while depression is a disease, grief is normal. Treating grief with antidepressants at best does not help and at worst simply postpones the normal healing process. Social support and psychotherapy is almost always the right treatment for grief, except in the few cases of abnormally prolonged or intense grief which have to be addressed as a special set of cases. But in any event, after loss of someone very close, something in the range of 9 to 15 months would be seen as a normal grief reaction.
Dr. Richard A. Friedman of Weill Cornell medical college in New York, writing in last week's New England Journal:
http://www.nejm.org/doi/full/10.1056/NEJMp1201794
--contrasts this standard wisdom about grief, which was how the existing DSM-IV categorizes the condition, with that of the working groups designing the new DSM-V. They intend to reclassify grief as a depressive disorder and suggest that after 2 weeks of mild depressive symoptoms, a bereaved person has crossed the line over into depression and should be treated as such. Dr. Friedman notes that there are zero scientific data to support this reclassification.
I have not been able to track down a source for this rumor, but I have heard murmurings that if the APA proceeds to issue the new DSM-V (apparently scheduled for next year) with this reclassification, some of the primary care physician organizations, including my own American Academy of Family Physicians, might vote formally to dissociate their members from DSM. This would be an unprecedented move as up till now, starting at least with DSM-III, all medical specialties have been willing to accept as gospel the disease classification proposed by the APA-- which by the way makes a ton of money from selling DSM as its proprietary product. But it is precisely due to the APA treating the DSM as its own private property and cash cow--along with the too-friendly association of leaders in psychiatry with the drug industry over many years--that has led to the present mess.
Friday, May 18, 2012
Hiding the Truth about Drugs: How Long Are Outcomes Delayed?
It has been a good while since I reported on drugs like epoetin, used to stimulate the body to make more red blood cells to counteract the anemia associated with end-stage kidney disease and cancer. My early post: http://brodyhooked.blogspot.com/search?q=dialysis-- commented mostly on the payment system that tempted dialysis and cancer docs to prescribe more of these drugs than was necessary or safe. But new information now suggests that the truth about the harms and lack of benefit of these drugs could have been known much sooner and many patients saved from bad outcomes. Sadly this is not the first such story in the history of the medicine-pharmaceutical industry relationship.
Dr. Daniel W. Coyne, a kidney specialist at Washington University-St. Louis, has both written a detailed paper and a briefer commentary about his research:
http://the-scientist.com/2012/05/14/opinion-misleading-drug-trials/
http://www.nature.com/ki/journal/vaop/ncurrent/full/ki201276a.html
I'm going to go into some detail about Dr. Coyne's findings as they illustrate several points, both about how scientific studies can be fudged to create a positive drug marketing message, and also how our bureaucracy works (or doesn't) to protect patient safety.
Before more recent research in the mid-2000s showing quite definitively that higher doses of epoetin-type drugs produced more strokes and other bad outcomes, the main research trial informing kidney guideline writers was the Normal Hematocrit Trial, conducted in 1996 and published in the New England Journal in 1998: http://www.nejm.org/doi/full/10.1056/NEJM199808273390903 This study was stopped early because of concerns that the higher doses of epoetin were causing more adverse reactions (more on that later). The journal article reported that on careful statistical analysis, there were no serious safety issues found, but that by contrast, quality of life of patients improved in the groups receiving the higher doses of epoetin (that is, those whose red blood cells achieved higher levels, which usually requires higher doses of the drug).
What Dr. Coyne did was simple. The drug company, Amgen, had to submit its own report of the study data to the FDA. As usually is the case, the FDA is under no obligation publicly to release these data and is indeed usually prevented from doing so by the proprietary nature of a company-sponsored study. Dr. Coyne requested the FDA data under the Freedom of Information Act, and was able to obtain the data after being kept waiting a mere 3-1/2 years (more on that later too). He then sat down and compared in detail the study data reported to the FDA to the same study reported in the medical journal in 1998.
First the safety data. According to the New England Journal, the primary study endpoint, death or non-fatal heart attack, showed no difference between the high- and lower-dose groups. But the reason that the authors concluded this was that the data monitoring board, that stopped the study early, insisted on a tighter threshold for statistical significance, reportedly to correct for the fact that the same data had undergone multiple prior statistical analyses. The usual threshold is P = 0.05, but with the demand for the stricter level of P = 0.008, there was no statistically significant difference. When Coyne looked at the data the drug company submitted to the FDA, he saw that with the unadjusted significance test, there were more adverse events in the higher-dose group, with P = 0.0119, which would normally be interpreted as quite a significant result.
Time out for a sidebar on early stoppage of clinical trials. As I previous blogged--for example, http://brodyhooked.blogspot.com/2011/03/how-honest-reports-of-research-can.html-- in the past, when drug trials are stopped early because a drug seems superior to the control, it is commonly found with later research that this result is spurious and that had the trial been continued to scheduled completion, there would have been no difference between drug and placebo (or other comparator). What we see in the case of the Normal Hematocrit Trial appears to suggest a double standard for industry-sponsored trials. If the trial is stopped early because the company's drug looks good, then that result is trumpeted as the truth, even if more study would cast doubt on that conclusion. If on the other hand a study is stopped early because the drug causes people to die, then the investigators get to move the goalposts and fudge the statistics, so that it turns out that those people did not really die after all. Without going into all the issues about whether data monitoring boards are truly independent of the study sponsors, and how early stopping can lead to misleading results even of the boards are totally kosher, it would seem a valid take-home lesson that we should authomatically be very skeptical whenever a drug trial is stopped early.
Now, back to the main story and the question of benefits. Dr. Coyne found that the study as reported in the New England Journal indicated benefit in quality of life for patients who had achieved higher red blood cell counts. Reportedly these findings were statistically significant at P = 0.03. When he reviewed the same data as reported to the FDA, he could find no evidence of any statistically significant improvement, with a single exception--it was indeed true that patients getting higher epoetin doses ended up requiring fewer blood transfusions.
So the bottom line--in 1998 the kidney dialysis community was told that higher epoetin doses, leading to higher red cell counts, posed no significant risk of harm and improved patients' quality of life. Based mostly on that one study, the kidney gurus issued several practice guidelines calling for higher levels of red cells, which in turn required docs to prescribe higher doses of epoetin. Around 2006-8, new data emerged suggesting that this was unsafe. In hindsight we now realize that the data from 1996-98 actually show the same thing, and indeed demonstrate lack of any benefit to boot; so between 1998 and 2008, however many dialysis patients were exposed to serious risks of harm, including death, with no corresponding benefit. In total, says Dr. Coyne, Amgen profited to the tune of $37B in total sales of epoetin.
Now for the bureaucracy piece. Dr. Coyne filed his FOIA request for the FDA data in January 2008. He finally received the data in July 2011. Two weeks before he received the data, the FDA issued new labeling for epoetin, calling for lower red blood cell levels. In its warning, the FDA accepted the statistical tests of the data on file, meaning that the FDA now belatedly rejected the statistical fixes that had been published in the New England Journal. He allows us to read whatever we want into the timing of these events.
In his opinion article, Dr. Coyne also reports having contacted some of the academic authors of the New England Journal version of the Normal Hematocrit Trial. They claimed to him that they had tried to insert the information that he later discovered into the published paper, but that the editors at the journal rejected those amendments. Dr. Coyne admits to skepticism, since these same authors published several later papers and also served on the kidney guideline committees, but never made any attempt to alter the impression given by the original publication.
In HOOKED, I mention a couple of other instances where patients suffered due to a delay in revealing the truth about the benefits and harms associated with a drug--Vioxx being the poster child, having caused an estimated 144,000 excess heart attacks during the years when its dangers should have been known. We now have to add epoetin to this dishonor roll.
Many thanks to Dr. Barbara Roberts, author of The Truth About Statins, for calling my attention to this work.
Dr. Daniel W. Coyne, a kidney specialist at Washington University-St. Louis, has both written a detailed paper and a briefer commentary about his research:
http://the-scientist.com/2012/05/14/opinion-misleading-drug-trials/
http://www.nature.com/ki/journal/vaop/ncurrent/full/ki201276a.html
I'm going to go into some detail about Dr. Coyne's findings as they illustrate several points, both about how scientific studies can be fudged to create a positive drug marketing message, and also how our bureaucracy works (or doesn't) to protect patient safety.
Before more recent research in the mid-2000s showing quite definitively that higher doses of epoetin-type drugs produced more strokes and other bad outcomes, the main research trial informing kidney guideline writers was the Normal Hematocrit Trial, conducted in 1996 and published in the New England Journal in 1998: http://www.nejm.org/doi/full/10.1056/NEJM199808273390903 This study was stopped early because of concerns that the higher doses of epoetin were causing more adverse reactions (more on that later). The journal article reported that on careful statistical analysis, there were no serious safety issues found, but that by contrast, quality of life of patients improved in the groups receiving the higher doses of epoetin (that is, those whose red blood cells achieved higher levels, which usually requires higher doses of the drug).
What Dr. Coyne did was simple. The drug company, Amgen, had to submit its own report of the study data to the FDA. As usually is the case, the FDA is under no obligation publicly to release these data and is indeed usually prevented from doing so by the proprietary nature of a company-sponsored study. Dr. Coyne requested the FDA data under the Freedom of Information Act, and was able to obtain the data after being kept waiting a mere 3-1/2 years (more on that later too). He then sat down and compared in detail the study data reported to the FDA to the same study reported in the medical journal in 1998.
First the safety data. According to the New England Journal, the primary study endpoint, death or non-fatal heart attack, showed no difference between the high- and lower-dose groups. But the reason that the authors concluded this was that the data monitoring board, that stopped the study early, insisted on a tighter threshold for statistical significance, reportedly to correct for the fact that the same data had undergone multiple prior statistical analyses. The usual threshold is P = 0.05, but with the demand for the stricter level of P = 0.008, there was no statistically significant difference. When Coyne looked at the data the drug company submitted to the FDA, he saw that with the unadjusted significance test, there were more adverse events in the higher-dose group, with P = 0.0119, which would normally be interpreted as quite a significant result.
Time out for a sidebar on early stoppage of clinical trials. As I previous blogged--for example, http://brodyhooked.blogspot.com/2011/03/how-honest-reports-of-research-can.html-- in the past, when drug trials are stopped early because a drug seems superior to the control, it is commonly found with later research that this result is spurious and that had the trial been continued to scheduled completion, there would have been no difference between drug and placebo (or other comparator). What we see in the case of the Normal Hematocrit Trial appears to suggest a double standard for industry-sponsored trials. If the trial is stopped early because the company's drug looks good, then that result is trumpeted as the truth, even if more study would cast doubt on that conclusion. If on the other hand a study is stopped early because the drug causes people to die, then the investigators get to move the goalposts and fudge the statistics, so that it turns out that those people did not really die after all. Without going into all the issues about whether data monitoring boards are truly independent of the study sponsors, and how early stopping can lead to misleading results even of the boards are totally kosher, it would seem a valid take-home lesson that we should authomatically be very skeptical whenever a drug trial is stopped early.
Now, back to the main story and the question of benefits. Dr. Coyne found that the study as reported in the New England Journal indicated benefit in quality of life for patients who had achieved higher red blood cell counts. Reportedly these findings were statistically significant at P = 0.03. When he reviewed the same data as reported to the FDA, he could find no evidence of any statistically significant improvement, with a single exception--it was indeed true that patients getting higher epoetin doses ended up requiring fewer blood transfusions.
So the bottom line--in 1998 the kidney dialysis community was told that higher epoetin doses, leading to higher red cell counts, posed no significant risk of harm and improved patients' quality of life. Based mostly on that one study, the kidney gurus issued several practice guidelines calling for higher levels of red cells, which in turn required docs to prescribe higher doses of epoetin. Around 2006-8, new data emerged suggesting that this was unsafe. In hindsight we now realize that the data from 1996-98 actually show the same thing, and indeed demonstrate lack of any benefit to boot; so between 1998 and 2008, however many dialysis patients were exposed to serious risks of harm, including death, with no corresponding benefit. In total, says Dr. Coyne, Amgen profited to the tune of $37B in total sales of epoetin.
Now for the bureaucracy piece. Dr. Coyne filed his FOIA request for the FDA data in January 2008. He finally received the data in July 2011. Two weeks before he received the data, the FDA issued new labeling for epoetin, calling for lower red blood cell levels. In its warning, the FDA accepted the statistical tests of the data on file, meaning that the FDA now belatedly rejected the statistical fixes that had been published in the New England Journal. He allows us to read whatever we want into the timing of these events.
In his opinion article, Dr. Coyne also reports having contacted some of the academic authors of the New England Journal version of the Normal Hematocrit Trial. They claimed to him that they had tried to insert the information that he later discovered into the published paper, but that the editors at the journal rejected those amendments. Dr. Coyne admits to skepticism, since these same authors published several later papers and also served on the kidney guideline committees, but never made any attempt to alter the impression given by the original publication.
In HOOKED, I mention a couple of other instances where patients suffered due to a delay in revealing the truth about the benefits and harms associated with a drug--Vioxx being the poster child, having caused an estimated 144,000 excess heart attacks during the years when its dangers should have been known. We now have to add epoetin to this dishonor roll.
Many thanks to Dr. Barbara Roberts, author of The Truth About Statins, for calling my attention to this work.
Thursday, May 17, 2012
Genetic Test Firms Steal Marketing Ideas from Pharma
Dr. Michael S. Wilkes of UC-Davis (and NPR), who has been eloquent in addressing issues around the ethics and professionalism of drug marketing, widened his gaze in an editorial a while back:
http://www.springerlink.com/content/0798016272844307/
He commented on another article in the journal on the marketing of genetic screening tests. It is generally agreed that while genetic testing can be very valuable for individuals or families known to be at high risk for an inherited disease, genetic screening tests aimed solely at showing a patient's statistical risk of developing multi-gene diseases such as diabetes or heart disease are seldom clinically useful and often quite misleading. Despite this a firm called Navigenics will very happily sell you one of this fishing-expeditiona genetic screening tests for a modest $999. What the research focused on was the fact that a national primary-care practice group, MDVIP, entered into a marketing agreement with Navigenics to promote this test to their patients, and that as part of this relationship, the company offered a free genetic screening test to these primary physicians, 1/3 of whom accepted the offer.
I'll pick up the commentarty from here in Dr. Wilkes's own words:
An offer of an incentive (in this case a free genetic test) from a new “collaborator” should clearly have raised questions for every one of the doctors. Even if any given doctor genuinely believed the test was in the best interest of a patient, it would be difficult to argue that the test ordering wasn’t influenced by a favor provided by Navigenics with an implicit expectation of reciprocity (“we did you a favor, now it is expected you will do us a favor by ordering this test on your patients”)....Is this type of social influence any different than offer of free drugs to doctors by pharmaceutical companies in an attempt to build loyalty?...
I wonder if any MDVIP physicians ever told their patients that they received a free gift by the very company that profited from the test the doctor was about to order—a test that has no proven value to the patient? Similarly, prior to testing, did the physicians include in their conversations with patients a discussion around informed consent? ...
It seems we have been round this issue before with pharmaceuticals and medical devices. As a profession, haven’t we decided that education developed by a company with a vested interest in the physician’s practice outcomes is not ethically or educationally appropriate? ...
Primary care doctors can either be part of the problem or we can be part of the solution by being vigilant and by self policing to avoid any actual or perceived conflicts of interest in order to maintain the trust of our patients and society. We also need to be informed consumers when it comes to our own education and avoid all commercial influence that seeks to promote profit at the expense of patient well being.
The usual hat tip to Rick Bukata and Jerry Hoffman's Primary Care Medical Abstracts for calling my attention to this article.
http://www.springerlink.com/content/0798016272844307/
He commented on another article in the journal on the marketing of genetic screening tests. It is generally agreed that while genetic testing can be very valuable for individuals or families known to be at high risk for an inherited disease, genetic screening tests aimed solely at showing a patient's statistical risk of developing multi-gene diseases such as diabetes or heart disease are seldom clinically useful and often quite misleading. Despite this a firm called Navigenics will very happily sell you one of this fishing-expeditiona genetic screening tests for a modest $999. What the research focused on was the fact that a national primary-care practice group, MDVIP, entered into a marketing agreement with Navigenics to promote this test to their patients, and that as part of this relationship, the company offered a free genetic screening test to these primary physicians, 1/3 of whom accepted the offer.
I'll pick up the commentarty from here in Dr. Wilkes's own words:
An offer of an incentive (in this case a free genetic test) from a new “collaborator” should clearly have raised questions for every one of the doctors. Even if any given doctor genuinely believed the test was in the best interest of a patient, it would be difficult to argue that the test ordering wasn’t influenced by a favor provided by Navigenics with an implicit expectation of reciprocity (“we did you a favor, now it is expected you will do us a favor by ordering this test on your patients”)....Is this type of social influence any different than offer of free drugs to doctors by pharmaceutical companies in an attempt to build loyalty?...
I wonder if any MDVIP physicians ever told their patients that they received a free gift by the very company that profited from the test the doctor was about to order—a test that has no proven value to the patient? Similarly, prior to testing, did the physicians include in their conversations with patients a discussion around informed consent? ...
It seems we have been round this issue before with pharmaceuticals and medical devices. As a profession, haven’t we decided that education developed by a company with a vested interest in the physician’s practice outcomes is not ethically or educationally appropriate? ...
Primary care doctors can either be part of the problem or we can be part of the solution by being vigilant and by self policing to avoid any actual or perceived conflicts of interest in order to maintain the trust of our patients and society. We also need to be informed consumers when it comes to our own education and avoid all commercial influence that seeks to promote profit at the expense of patient well being.
The usual hat tip to Rick Bukata and Jerry Hoffman's Primary Care Medical Abstracts for calling my attention to this article.
Tuesday, May 15, 2012
Bipartisanship in Congress, in Support of Pharma and Device Industries
It's often said today that Congress is totally dysfunctional and cannot agree on anything due to the huge partisan culture war. Well, the good news is that there's bipartisan cooperation on at least one issue. The bad news is that it's all in favor of handing the foxes at the pharmaceutical and medical device industries the key to the FDA henhouse.
The estimable Merrill Goozner: http://gooznews.com/?p=3914--has blogged about the latest renewal round of the Prescription Drug User Fee Act, where drug firms agree to pay a lot of the freight for running the FDA's drug approval process, and almost always manage to wring out favorable concessions in exchange for their largesse. Among the Christmas list the industry wants this time, and that Congress, well primed by the lobbyists, is apparently ready to hand them, are:
The solution, as we have known for a good while, is to stop depending on the drug industry to fund the FDA--though replacing drug bucks with taxpayer bucks won't make that army of lobbyists go away (meaning that at some point or other, campaign finance reform is desperately needed as well).
NOTE ADDED 5/18: A kind colleague at Consumers Union just sent me two links that are very useful in relation to this issue-- first, a Public Citizen fact sheet regarding device regulation:
http://www.citizen.org/documents/30-things-you-need-to-know-about-medical-devices-approvals-the-industry-and-safety.pdf
--and next, a Twitter discussion from the Safe Patient Project at Consumers Un ion regarding the pending legislation in Congress and how it fails to protect patients:
http://twitter.com/#!/cusafepatient
The estimable Merrill Goozner: http://gooznews.com/?p=3914--has blogged about the latest renewal round of the Prescription Drug User Fee Act, where drug firms agree to pay a lot of the freight for running the FDA's drug approval process, and almost always manage to wring out favorable concessions in exchange for their largesse. Among the Christmas list the industry wants this time, and that Congress, well primed by the lobbyists, is apparently ready to hand them, are:
- More use of surrogate markers to approve new drugs, without demanding proof that the actual diseases that affect people get any better (e.g., a drug that lowers blood sugar but does nothing to prevent heart attacks or strokes or blindness from diabetes)
- Complete gutting of the reforms called for in the recent Institute of Medicine report to toughen requirements for testing new devices for safety
The solution, as we have known for a good while, is to stop depending on the drug industry to fund the FDA--though replacing drug bucks with taxpayer bucks won't make that army of lobbyists go away (meaning that at some point or other, campaign finance reform is desperately needed as well).
NOTE ADDED 5/18: A kind colleague at Consumers Union just sent me two links that are very useful in relation to this issue-- first, a Public Citizen fact sheet regarding device regulation:
http://www.citizen.org/documents/30-things-you-need-to-know-about-medical-devices-approvals-the-industry-and-safety.pdf
--and next, a Twitter discussion from the Safe Patient Project at Consumers Un ion regarding the pending legislation in Congress and how it fails to protect patients:
http://twitter.com/#!/cusafepatient
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