Saturday, June 30, 2007
Friday, June 29, 2007
Saturday, June 23, 2007
More recently a post from Retired Doc made the point better than I did:
Over thirty years ago another medical publication dealt with a purported increase in cardio vascular deaths from an oral diabetic medication. The University Group Diabetes Program (UGDP) was presented at the June 1970 meeting of the American Diabetes Association. Data presented indicated that tolbutamide increased cardiovascular deaths by over two and half times. (RR of 2.61, CI-1.29-5.27)…….
The UGDP study in many ways presented more robust evidence that the Nissen article. It was a randomized clinical trial (Yes Virginia, clinical trials were done before the folks from Canada descended from the mountain with the precepts of EBM carved into stone) and the R.R. was greater than 2, a number less than which many epidemiologists put little weight as small RR's can be pushed around by small biases. Putting too much emphasis on medical analyses which derive RR's less than 2 has been a issue of interest to me for some time and I have ranted on about that before.
It’s a shame about medical reporting in the popular media. Medical information, more often than not, is presented superficially, as a series of isolated sound bites without perspective, proportionality or regard for prior research.
Friday, June 22, 2007
At that time I pointed out that although anticoagulant treatment of VTE is not “evidence based” in a strict sense, the totality of evidence in favor of anticoagulant treatment is compelling. I also cited this paper which is a must read if one wants a balanced and thorough analysis of the literature on this subject.
Dr. Poses, discussing conflicts of interest surrounding the debate, focuses on money. I believe, though, he placed too little emphasis on Dr. Cundiff’s non-financial conflict which I mentioned in my 2005 post.
Thursday, June 21, 2007
The Journal does a disservice to its readers when it presents a homeopathic jargon filled discussion as if a scientific discussion is taking place. There was no editorial explaining the reasoning behind publishing such an article. One of the characteristics of science is its coherence. The sciences of pharmacology, physiology and toxicology build upon and are consistent with the laws of chemistry and physics. To talk about diluting a substance to the point where it is undetectable and then explaining how it works to heal flies in the face of the principles of those disciplines. It is too late to write a letter to the editor but I hope someone did.
Well, eventually some people did: Treating Critically Ill Patients with Sugar Pills. Like Retired Doc, the letter writers are surprised Chest would accept such a paper.
The authors of the paper, in effect, admit that the study drug is mere water with this statement:
Since the potentiation (dilution and vigorously shaking) of the study drug beyond the Avogadro number imposes no interaction with the patient’s metabolism, and due to the low cost of the drug, its use in the ICU may be beneficial, minimizing morbidity and mortality.
The fact that this paper appeared in Chest impresses me with just how deep pseudoscience has penetrated the mainstream. I’d have expected something like this in BMJ, but not the revered Chest!
Wednesday, June 20, 2007
According to a CNN report the practice is known as diabulimia and has, with the help of Internet message boards, become increasingly popular, tried by as many as one third of type I diabetic women in the U.S. The report highlights the addictive nature of the problem and the risk of microvascular complications when the behavior is sustained over time.
Unfortunately the piece falls short in explaining diabulimia’s effects on the body with statements such as: “When sugars are high, the kidneys work overtime to filter the excess glucose from the blood.” Not exactly. Just the opposite, if anything. The kidneys work overtime NOT to excrete glucose by revving up the process of proximal tubular reabsorption, the capacity of which is exceeded in hyperglycemia due to increased concentration of glucose in the glomerular filtrate. Hyperfiltration does in fact occur in early diabetic nephropathy, though lacking in any teliologic explanation that I am aware of and involving mechanisms incompletely understood.
Added to the risk of microvascular disease is the threat of ketoacidosis. If weight loss, especially rapid weight loss is one’s goal then ketosis, the “smoke” of burning fat, might be considered desirable. But the ketosis of uncontrolled type I diabetes differs in at least one important respect from that of fasting in the normal individual due to inability of a self-regulating feedback mechanism in type I diabetes as will be explained below.
Insulin’s anti-ketotic mechanism involves two molecular sites, the first of which is the adipocyte and the second of which is the mitochondrial membranes in the hepatocyte. Insulin’s action on the adipocyte is the inhibition of hormone sensitive lipase (HSL). In insulin lack (or, in stress, a reduction in the ratio of insulin to counter-regulatory hormones) HSL is activated, leading to breakdown of stored triglyceride to glycerol and free fatty acid (FFA). Insulin lack at the level of hepatocytes creates a “ketogenic mode” in the liver which allows the beta oxidation of FFA to ketone bodies. This occurs via activation of carnitine palmitoyltransferase-1 (CPT-1), an enzyme which mediates attachment of a carnitine molecule to the fatty acid thus enabling entry into the mitochondria for beta oxidation.
Non type 1 diabetics have endogenous insulin. Fasting in such individuals causes ketosis. However, ketone bodies and FFAs feed back on the pancreas causing it to secrete a small amount of insulin, enough to partially inhibit HSL, thus limiting the supply of FFA to the liver and preventing ketoacidosis. (Exceptions are lactation, late pregnancy and some instances of acute alcoholism, states in which this system of checks and balances is defective). In type 1 diabetics this feedback mechanism is unavailable due to an absolute, or nearly absolute, lack of endogenous insulin.
Via Kevin M.D. and Clinical Cases and Images.
Sunday, June 17, 2007
There are 3 phrases that should and can no longer be said about the US health care system without qualification, embarrassment, criticism, or even denunciation: "The United States has the best health care system in the world," "Health care is special," and "New is better."
The solution could hardly be simpler: any continuing medical education that is paid for by the drug industry should not be accredited. Drug companies could still pay for any educational event, article or pamphlet they choose, but their courses and materials would no longer bear the imprimatur and implied credibility of accreditation.
Doctors, in turn, would be encouraged to seek medical education from sources that are not financed by drug companies. A renewed commitment to unbiased education would allow doctors to learn about drug risks sooner.
So, we are to believe that drug company support for accredited CME keeps doctors from learning about the risks of drugs. I wish Daniel Carlat, the author of the piece and a professor at Tufts Medical School, would provide evidence to back that incredible claim. The adverse lipid effects of Avandia, for example, were well known for several years. (Some time ago I linked to this review which cited Avandia’s well known adverse effects).
Carlat seems to believe, as implied by the title of his OP-ED piece, that drug companies have a conflict of interest concerning information about adverse drug effects. But common sense and history suggest the opposite: that it’s very much in industry’s interest for doctors to be informed about the hazards of drugs. It would certainly have been in the interest of American Home Products for doctors to know the hazards of Fen-phen. Johnson and Johnson is still paying for doctors’ failures to heed their package information and repeated letters about the hazards of cisapride. Pharmaceutical companies know all too well that if the message about drug hazards could be communicated effectively and responsibly they would not have to pay, in money and reputation, for so many doctors’ mistakes.
There must be a reasonable middle ground. Drug companies should not become the primary educators of doctors. But with appropriate safeguards industry support for CME can be beneficial.
Tuesday, June 12, 2007
The first question is clinical: what are the benefits and harms of rosiglitazone as a treatment of Type 2 diabetes, and therefore for which patients under what circumstances should this drug be used?
The second question is about policy: what barriers, if any, have prevented physicians and patients from getting the best possible answer to the first question, and what can be done about them?
My take is that the first question is complex, and must be answered in light of what we know about all the other available options for type 2 diabetes. The meta-analysis has its problems and must be considered hypothesis generating. As I posted here there seem to be disparate effects on macrovascular disease between the two available TZDs, pioglitazone (Actose) and rosiglitazone (Avandia) which have a plausible basis due to differing effects on lipids and differing molecular mechanisms.
So how can we summarize and compare macrovascular outcomes associated with various treatments for DM-2?
Pioglitazone, the only TZD available other than rosiglitazone appears to reduce macrovascular events.
In the UKPDS metformin decreased stroke and all cause mortality in obese patients, but the overall results for metformin were not internally consistent.
Insulin therapy has not been demonstrated to halt macrovascular disease. There is evidence that intensive insulin treatment may in fact be associated with increased macrovascular disease but this is controversial.
The first generation sulfonylurea tolbutamide is associated with a marked increase in cardiovascular mortality in the UGDP trial. Other sulfonylureas carry the cardiovascular warning although they have not been similarly studied.
The clinical bottom line of all these findings is that macrovascular disease is an elusive target in DM-2 and choices of agents at this time must be governed by limited information.
Concerning the second question, barriers on both sides have prevented physicians and patients from getting the best possible answer regarding Avandia. GSK may have suppressed information and its defenders appear to have engaged in personal attacks on the lead author of the NEJM meta-analysis. On the other hand, the timing and manner of the release of the NEJM meta-analysis suggest a case of orchestrated hype.
Both sides have explaining to do. Although Dr. Nissen’s testimony in the Waxman hearing seemed evasive, he was frequently interrupted and not given a chance to elaborate on his answers. He should have the opportunity to convince us that the meta-analysis was not agenda driven.
Sunday, June 10, 2007
1999 was about the time pain management became politicized and activists were beating up on doctors for under treating pain. They pummeled us with arguments based 90% on dogma and 10% on science. They told us that the patient’s numeric rating of pain was “the fifth vital sign.” They redefined the concept of addiction to suit their agenda and told us that most instances of drug seeking behavior were in fact “pseudo addiction”, supposedly an indication to give more narcotics. A stable patient verbalizing “eight out of ten” pain was a medical emergency and a mandate for narcotics. Respiratory hazards were downplayed.
At least one expert shares my view. In a recent point-counterpoint in Internal Medicine News William O. Witt, M.D. from the University of Kentucky Medical Center at Lexington opined that today’s widespread opiate use is not evidence based and poses an increasing public health risk. He notes: “Whereas no one is advocating the elimination of opioids as a tool for treating chronic nonmalignant pain, we should demand at least the same rigor that we demand for other treatments.”
In cardiac surgery patients a fall in the platelet count is expected in the first four postoperative days and is unlikely to be HIT, whereas HIT is much more likely the cause of thrombocytopenia on days 5-14, often manifested as a second fall during recovery from the initial thrombocytopenia.
Unusual presentations are highlighted (thrombosis before overt thrombocytopenia, systemic inflammatory reactions moments following heparin exposure in patients with pre-existing antibodies, adrenal crisis due to adrenal hemorrhage).
Disseminated intravascular coagulation has been reported in 10-20% of cases of HIT, potentially confounding both the diagnosis of HIT and the laboratory monitoring of patients treated with alternative anticoagulants.
Advantages and disadvantages of the various alternative anticoagulants are discussed.
The approach to patients with possible HIT but isolated thrombocytopenia (i.e. no thrombosis) is controversial. Use of the clinical probability score is helpful, and in some patients who merit treatment beyond merely stopping heparin, the authors favor lower dose regimens of alternative anticoagulants.
The duration of alternative anticoagulant therapy and the optimal timing to initiate warfarin are discussed.
Friday, June 08, 2007
DB of Med Rants writes:
This should remain a scientific debate. Unfortunately it has become a political debate. Guess what the culprit really is - $$$$$$$$.
Yes, this should have been a scientific debate. Unfortunately, the way the meta-analysis was presented, scientific debate never stood a chance. Politics and money have, to a degree, aligned on opposite sides of the controversy and both are culpable.
Dr. Poses wants to “call off the dogs”. But, unfortunately, once dogs on both sides of the issue have been released into the arena of public debate it may be too late too call them off.
What we need to be asking is how scientific discussion got stifled in the first place. Let’s go back to the beginning. We don’t have details about what transpired between Dr. Nissen and politicians on Capital Hill in the weeks leading up to the release of the meta-analysis. We do know that the meta-analysis and an accompanying editorial by drug safety crusaders with an agenda to reform the FDA were released on line for open access ahead of print without sufficient public health urgency. Worse, according to this Heartwire report the release was timed to precede by two days an anticipated FDA safety report on Avandia. (By Dr. Nissen’s own admission in his testimony before Waxman’s congressional hearing the FDA had all the data he had and more). Moreover, according to Dr. Scott Gottlieb’s Wall Street Journal article Waxman issued a press release immediately after the release of the meta-analysis, suggesting that the whole hyped up mess was orchestrated. (I was unable to find a press release from Waxman on line. However, this press release from the Senate Finance Committee, issued the same day as the meta-analysis, seems a little too detailed and lengthy not to have been planned. Also, this press release from Senator Kennedy appeared the day after the meta-analysis, and this one from Cleveland Clinic appeared the day of).
So I’ll reserve final judgment, as there are some unknowns here, but from where I sit this looks like a case of calculated hype. Among many potential players we don’t know which ones played major roles. And though there are many potential conflicts of interest we can only speculate on the actual ones. Dr. Nissen’s situation, for example, is complex. Were his conflicts political? I don’t know his political leanings. Was it a case of self promotion, or zeal to trump the FDA? (By his own admission the FDA was better equipped than he to analyze Avandia’s risk, so why didn’t he just wait and let the agency do its work?). Financial considerations could have been at play. Dr. Nissen has had ties to Takeda pharmaceuticals, makers of Avandia’s direct competitor Actose, the only other TZD approved in the U.S. (According to this Fox News piece new prescriptions for Actose jumped 50% following release of the meta-analysis).
Unfortunately this mess is self-reinforcing. Propaganda begets propaganda, and there’s been plenty on both sides. I have no pharmaceutical industry ties. Dr. Poses and others have done a commendable job of exposing the pharmaceutical industry’s dirty tricks. The focus of my blog has been non-industry related conflicts of interest. This is not out of any desire to defend the drug companies or minimize problems related to their influence. It is an attempt to balance the debate by addressing a selective outrage which seems to blame industry for virtually all the problems facing health care and under-recognizes other conflicts.
More here from Kevin M.D.
Giuliani said he would give families a $15,000 tax credit to purchase private insurance policies and allow them to keep whatever credit remains as an incentive to purchase cost-effective plans. "If we can empower 30 million, 40 million, 50 million and eventually 100 million Americans to be able to go out and make these choices, you're going to have the free market accomplish the thing that only a free market can accomplish -- and that is, lower costs and better quality," Giuliani said in an interview on the Sean Hannity radio program.
Via Kaiser Network.
Thus, from its roots as a patient-centered, education-oriented year of learning, the medical internship has evolved into a laboratory-centered, algorithm-oriented, technology-driven, computer-dependent, Internet-based, “treat first, diagnose later” training program. Consequently, we are exchanging sleep-deprived healers for a cadre of wide-awake technicians who cannot take an adequate medical history, cannot perform a reliable physical examination, cannot critically assess information they gather, cannot create a sound management plan, have little reasoning power, and communicate poorly.
Read the rest.
Cardiac channel disorders continue to garner interest. Despite the discovery of new mutations leading to the long QT syndrome (LQTS) some 25% of patients with LQTS have no identifiable genetic abnormality. Brugada syndrome is increasingly well understood. The channelopathies of Brugada syndrome appear to cause a gradient between endocardium and epicardium caused by disparities in phase 1 of their respective action potentials. In contrast to the LQTS, relatively few patients with Brugada syndrome (20%-30%) have an identified genetic abnormality.
One study referenced in the review is interesting, to me anyway, not because of any immediate clinical relevance but because it’s an example herbal research done right. Investigators created a Brugada syndrome phenotype in isolated perfused canine right ventricular tissue. Drawing on prior research showing that dimethyl lithospermate B (dmLSB), a minor component of the root extract of the Danshen plant, is capable of decreasing inactivation of the sodium current INa, the researchers demonstrated reversal of the Brugada phenotype by adding dmLSB to the perfusate. Basic research such as this may pave the way for novel drug therapies for cardiac channelopathies
Recent research in Brugada syndrome has also made it increasingly evident that the electrocardiographic findings may fluctuate over time, often necessitating multiple tracings to diagnose, classify and risk stratify patients.
Genetic abnormalities, both germ line and somatic, also underlie non lethal conditions. Recent findings relating to genetic causes of sick sinus syndrome and somatic mutations in atrial fibrillation were presented.
Finally, nonantiarrhythmic drugs are increasingly being found to prevent arrhythmias. A meta-analysis cited in the review found that treatment with angiotensin converting enzyme inhibitors and angiotensin receptor blockers decreases the new onset of atrial fibrillation in patients with and without heart failure. The review cited prior studies indicating that statin drugs prevent atrial fibrillation and a recent study of patients with coronary artery disease and implanted defibrillators showing that administration of 80mg daily of atorvastatin decreases episodes of device intervention by 50%.
Scrupulosity in dealing with pharmaceutical companies may have unappreciated costs and unintended consequences
Thursday, June 07, 2007
One of the panel members mentioned that Dr. Scott Gottlieb’s Wall Street Journal piece is now on line (in full text) at the American Enterprise Institute web site. He writes:
NEJM said it rushed to post the study on the Web because of its medical importance, but the FDA, which would need to act on any safety issues, wasn't even given a heads up about the study's publication or its findings. Rep. Henry Waxman (D., Calif.), however, seems to have known in advance that it was coming because he issued a substantive press release immediately after the study was posted online. He was even ready with the date and location of oversight hearings aimed at probing the FDA's "handling" of the drug safety issues.
Under questioning from Congressman Waxman Dr. Nissen (author of the NEJM meta-analysis) confirmed that he had informed congress about the meta-analysis. Dr. Nissen was questioned extensively by multiple members of the committee. When asked repeatedly why he conferred with members of congress and did not notify the FDA he talked around the question with responses such as “I put people above politics”. The only reason he seemed able to give was that he wanted help in gathering data for his research.
Nissen indicated that he provided his preliminary analysis on Avandia to members of Congress in February. Why didn’t he go to the FDA? Because “that’s not how it’s done.” He also pointed out that they already had the data. True, but they didn’t have the results of the meta-analysis.
In his defense of not going to the FDA Nissen testified that the FDA already had much more data than he had access to. Well, if his purpose was to get missing data, again it begs the question, why didn’t he go to the FDA? Apparently because the FDA is not allowed to release that information. News to me, but perhaps so. But if the FDA had everything he had and more why not wait for them to release their analysis before submitting his meta-analysis to NEJM?
What bothers me more than anything is that a clinical investigator goes to politicians for help in researching for a scientific publication. I had to replay the video two or three times to be sure I heard correctly. Astounding. I’d say that fact should have been included in Dr. Nissen’s disclosure statement.
Wednesday, June 06, 2007
Putative active ingredients included the patients' "openness to the mind-body connection", consultational empathy, in-depth enquiry into bodily complaints, disclosure, the remedy matching process and, potentially, the homeopathic remedies themselves.
This paper, largely promotional and uncritical, (the lead author practices homeopathy and the paper contains numerous homeopathy promoting statements) lends insight into the mind of homeopathic practitioners. There is, for example, this revealing statement:
The relative contributions of remedy and context cannot be distinguished either in real-world homeopathy or in this study. Most homeopaths behave as if the remedy is the main active ingredient.
So, the authors seem to acknowledge that any benefits of homeopathy likely derive as much from the empathy and engagement of the practitioner as from the medication (the “remedy”) itself.
So what’s the take home message here? How do these observations inform the debate on homeopathy? From the paper’s abstract:
These findings counsel against the use of placebo-controlled RCT designs in which both arms would potentially be receiving specific active ingredients. Future research in homeopathy should focus on pragmatic trials and seek to confirm or refute the therapeutic role of constructs such as patient "openness", disclosure and homeopathicity.
In other words, don’t study the efficacy of the homeopathic medication with other variables (e.g. practitioner engagement and empathy) controlled. This mindset is already pervasive in much of CAM “research”. Orac provided a good example recently, citing a study of the benefits of Tai Chi which failed to control for the effects of exercise.
I wouldn’t be all hot and bothered, merely amused, by this paper were it not for this statement from Biomed Central Complementary and Alternative Medicine’s masthead: BMC Complementary and Alternative Medicine (ISSN 1472-6882) is indexed/tracked/covered by PubMed, MEDLINE, CAS, Scopus, EMBASE and Google Scholar. Which means, of course, that innumerable woo based papers will be legitimized and, worse, find their way into systemic reviews and meta-analyses.
According to the lawsuit, Christy was admitted to Thomas Memorial on May 24, 2006, and was treated for chronic diverticulitis. Kyer performed an elective sigmoid resection by laparoscopic means. Christy was released on May 28, 2006. However, on June 2, 2006, he went to the emergency room, complaining of severe abdominal pain. He was admitted and a CT scan revealed a free intraperitoneal error.
Tuesday, June 05, 2007
What’s ironic is that this is the second time BMJ, widely regarded as a scholarly journal and a champion of evidence based medicine, has been called out for faulty reporting. The other instance occurred in 2005 when a BMJ news story alleged that damaging drug company documents “went missing” in a product liability case. Following a complaint from the company BMJ, after investigating the matter, issued a correction and apology.
Via Kevin M.D.
Monday, June 04, 2007
But many others, including those in the medical community, are hoping Moore will help make a difference. "Anything—including a film—that can bring this issue into the public eye is good for the debate," says heart surgeon Dr. William Plested, president of the American Medical Assn. "So, I'm cheering on Michael Moore, even though I haven't seen the film."
Via Kevin M.D.
The New York Personal Injury Law Blog reports that the plaintiff’s attorney
…..scoured his blog for helpful information, much the way any attorney would review writings produced by a witness for the other side. She found a post where Flea referred to Nelson’s Pediatrics as the bible of pediatrics. (I have the 11th ed. from 1979 on my own bookshelf.) So she asked him on the witness stand if he considered Nelson's the bible for pediatrics. He said no. Lawyers call that a "prior inconsistent statement" that allows us to confront the witness with the other statement. That meant asking him if he was Flea and confronting him with the blog posting.
We tend to regard clinical topics as safe blogging material. Flea’s case tells us that’s not necessarily so. Clinical opinions, or opinions about text books and other clinical references, particularly strong declarative statements, could be used against you as a defendant when the clinical topic is relevant to the case you’re defending.
What’s a blogger to do? First and foremost, whether you’re anonymous or open don’t be dogmatic or absolute. Clinical medicine, after all, isn’t that way. It is subtle and nuanced, so be subtle and nuanced in your discussions. Be careful how you describe clinical references. Up to Date may be helpful at the point of care but it’s not “authoritative”. Harrison’s textbook may be a useful reference but it’s not “the bible”.
Kevin and his commenters have more.
Sunday, June 03, 2007
In intention-to-treat analysis, the response of the two groups (63 treated and 28 control) clearly diverged by day 7, with twice the proportion of treated patients achieving a 1-point reduction in LIS (69.8% vs 35.7%; p = 0.002) and breathing without assistance (53.9% vs 25.0%; p = 0.01). Treated patients had significant reduction in C-reactive protein levels, and by day 7 had lower LIS and multiple organ dysfunction syndrome scores. Treatment was associated with a reduction in the duration of mechanical ventilation (p = 0.002), ICU stay (p = 0.007), and ICU mortality (20.6% vs 42.9%; p = 0.03). Treated patients had a lower rate of infections (p = 0.0002), and infection surveillance identified 56% of nosocomial infections in patients without fever.
A wide range of etiologies of ARDS was represented. 41% had pneumonia and 13% had extrapulmonary sepsis. Extrapulmonary and direct pulmonary etiologies of ARDS were equally represented.
A related editorial, Corticosteroids for ARDS: Just do it!, is strongly in favor of the protocol and cites other supporting literature. It stresses counter measures against the adverse effects of corticosteroids such as routine infection surveillance and glycemic control.
Saturday, June 02, 2007
I would encourage anybody to write a blog if they have something interesting to say and add value to the online conversation. Just be smart about it. Write to share and educate not to blow off steam. We live in a Google world. What you post online today can come back tomorrow to haunt you.
For me, not blowing off steam doesn’t mean we shouldn’t express strong opinions. My rule is to try and back up opinions with evidence, avoid personal attacks and avoid references to local health care issues.
- Write as if your boss and your patients are reading your blog every day
- Comply with HIPAA
- Do not blog anonymously. List your name and contact information
- If your blog is work-related, it is probably better to let your employer know
- Use a disclaimer, e.g. " All opinions expressed here are those of their authors and not of their employer. Information provided here is for medical education only. It is not intended as and does not substitute for medical advice."
Whether it’s best to blog anonymously is a point of controversy, but recent events have shown us that the veil of anonymity is thin.
The workaround takes advantage of the fact that Google’s cache periodically updates its snapshot of your web page. Simply modify the post or posts in question in a way that removes content you consider risky or renders it harmless. Then wait a few days for Google to update the cache (you can search the cached content to verify that the update took place). Then delete. The same strategy works for blog lines.
The Internet Archive Wayback Machine is more problematic because it saves all the old copies of your site. If you’re lucky, the objectionable content will miss the archive, which updates at discrete points in time at variable intervals. Fortunately it’s fairly difficult to find specific content in the Wayback Machine. It’s not retrieved by Google, and the Wayback Machine itself can’t be searched by text or titles---the url must be entered.
Friday, June 01, 2007
But new reports go one step further--suggesting that FDA whistleblowers coordinated with politicians critical of the agency and the study authors to get damaging data into the public arena before the FDA could issue a safety statement on rosiglitazone.
The Heartwire report is based on the Wall Street Journal editorial I linked here. That editorial was written by former FDA deputy commissioner Scott Gottlieb. In an earlier post I puzzled over NEJM’s decision for early open access release of the meta-analysis and related editorial. A timeline of events according to the Heartwire report, based on the WSJ editorial, suggests a reason for the decision: since the print release of the meta-analysis and editorial was not due until June 14 it was the only way to upstage the FDA safety evaluation, due out just two days later, May 23. The choice of Bruce Psaty and Curt Furberg to write the editorial would dovetail nicely with such a strategy, as these authors are well known critics of the FDA.
The question of the early open release nags. If not to discredit the FDA then why? According to the Heartwire report:
Gottlieb says the NEJM claims to have made the decision to publish quickly because of the medical importance of the research but, if that were the case, he wonders why it did not inform the FDA about its publication or the findings.
Indeed. Medically important research, maybe, but not a public health emergency. If the meta-analysis findings are to be believed the number needed to harm for rosiglitazone must be on the order of 1000, and that’s over months to years of treatment. If that’s the standard for early release it’s a new standard. Under such a standard virtually every paper in clinical epidemiology which shows a significant difference in event rates would merit early release.
Rush Limbaugh's term for the sensational, scandal-seeking, and agenda-driven coverage that is typical of the national press corps in America. Limbaugh draws an analogy between the media who cover a story with a barrage of unfair cheap shots before moving on to the next flavor of the month and an inner city gang that drives by and sprays a target with gunfire and then moves on to their next target.
Media coverage of Avandia that’s fair, that has any depth at all, would have to include these little known facts:
1) The ADOPT and DREAM studies did not show increased macrovascular risk for rosiglitazone. The small increase in cardiac events was attributable to heart failure precipitated by renal and metabolic effects leading to fluid retention and not indicative of an adverse macrovascular effect. The risk of fluid retention was previously known and is adequately addressed in current product labeling.
2) According to a recent Heartwire piece an interim safety review of the ongoing RECORD study reveals no adverse safety signal for rosiglitazone.
3) The same Heartwire article also notes that the data safety monitoring boards of two other ongoing rosiglitazone studies (BARI 2D and ACCORD) have found no safety concerns.
4) The landmark UGDP study, a randomized prospective trial of cardiovascular outcomes associated with various treatments for type 2 diabetes, showed a highly statistically significant increase in cardiovascular death associated with the first generation sulfonylurea tolbutamide compared to placebo or insulin. This was (according to product labeling) a greater than two fold increase in cardiovascular death, mind you, a finding much more concerning than those of the Avandia meta-analysis which found no statistically significant increase in cardiovascular death. Whether the currently popular new generation sulfonylureas carry similar risk is controversial---head to head studies haven’t been done---but the newer sulfonylureas carry the boxed warning. Here is the one for glimepiride (Amaryl). (Why aren’t the media mentioning a possible two fold increase in risk of cardiovascular death? Shouldn’t they be advising patients taking sulfonylureas to ask their doctor?).
Not all newspaper reports were so distorted. One Wall Street Journal report apparently got some things right. And the drive-by label is not restricted to newspapers. It could apply to medical journals and blogs when the shoe fits.