March 2010 Archives

Not only an inspiration for a porno, The Amazing Dr. Clitterhouse (1938) is highly entertaining noir-life. While researching the criminal mind, the titular doc (Edward G. Robinson) gets mixed up with a top fence (Claire Trevor) and her thug sidekick, Rocks Valentine (Humphrey Bogart). An ensuing power struggle between the charismatic doc and Rocks escalates the criminal stakes to murder.

Stanford rightly shut down Dr. Michael Dake's jugular stent program for patients with multiple sclerosis. Dake, a multi-board-certified physician* and professor of cardiothoracic surgery at Stanford, had placed jugular-vein stents in 40 patients with MS, according to the WSJ, on the basis of Internet-fueled enthusiasm for the implausible idea that MS is due to venous insufficiency.

The hypothesis is the "Big Idea" of Italian vascular surgeon, Paolo Zamboni—who has documented venous-outflow anomalies in patients with MS. These findings were the basis for Zamboni's uncontrolled study of venous angioplasty in 65 patients with MS, which was reported last year. Despite the fact that the study yielded mixed results, it apparently produced unbridled zeal in chat rooms, and the zeal found its way to Dake.

The WSJ reports that a "number" of Dake's patients experienced neurologic improvement after jugular angioplasty or stenting (thank you, placebo effect and the highly variable nature of MS), but 1 patient died of cerebral hemorrhage, and the stent of another became dislodged in his heart. The WSJ implies that Stanford and UCSF neurologists were instrumental in getting Dake's stent program shut down in December.

MS, which is currently treated with evidence-based disease-modifying therapies like interferon beta, is believed to be an autoimmune disorder. While cerebral venous insufficiency may be documentable in MS, it is unknown if this is a consequence of the disorder or merely an epiphenomenon. It is unlikely to be the cause.

* But not a neurologist.

Image of neck veins from Gray's Anatomy (1918).

...the gap in Medicare prescription-drug coverage will have been closed for 5 years, if all goes according to what's stipulated in the Patient Protection and Affordable Care Act and the Senate's follow-up reconciliation bill.

Because the newly signed healthcare reform will be financed, in part, by whatever can be squeezed out of Medicare and its growth, several changes to the government's insurance for the elderly will take place during the next 10 years. Changes are supposed to occur in concert with the following significant cuts in Medicare spending: 

Medicare funding to…	Cuts, Billions of $
Hospitals	134.9
Advantage plans*	120
Nursing homes	14.6
Home health agencies	42.1
Hospices	7.7
Total	464.6

Much of the Act's relevance to Medicare can be found in Title III, "Improving the Quality and Efficiency of Healthcare." But for cheaters (or the merely sane), relevant nuggets can be obtained from the Democratic Policy Committee and the NYT.

In the year 2010:

• Medicare recipients who hit the so-called donut hole in prescription coverage (between $2830 and $6440 in out-of-pocket drug costs) will receive a $250 rebate.
• The DHHS will receive additional resources to develop a "national quality strategy" and to support the measurement, improvement, and endorsement of Medicare quality (along with Medicaid and CHIP quality). The strategy should be submitted by January 1, 2011.
• Reductions in Medicare reimbursements to hospitals, nursing homes, home health agencies, and hospices will begin. But payment protections to key facilities with a low volume of Medicare recipients (eg, small rural hospitals) will be extended.

In the year 2011:

• Medicare recipients who hit the donut hole will receive a 50% discount on brand-name drugs. The discount will increase incrementally during the next 9 years. But Medicare subsidies will be reduced for beneficiaries in higher income brackets (individuals, $85,000; couples, $170,000).
• Annual wellness visits for Medicare beneficiaries will be free, and cost-sharing for preventive services will be eliminated.
• Primary care physicians and general surgeons will receive a 10% increase in Medicare reimbursement.
• In July, access to primary care will be increased by adjusting the Medicare Direct Graduate Medical Education program.
• Drugmakers will have to provide discounted drugs to Medicare recipients.
• To reduce costs and increase quality of care, a new Center for Medicare and Medicaid Innovation will be established to assess innovative payment and service-delivery methods.
• A new Community Care Transitions Program will provide transition services to "high-risk" Medicare recipients.
• Benchmarks for Medicare Advantage* payments will be frozen at the 2010 level. Benchmarks will then be reduced further during the next 3-7 years in "high-cost" areas. (It is speculated that the 10 million participants in these plans will face higher premiums or reduced benefits.)

In the year 2013:

• To promote Medicare payment bundling, hospitals, physicians, and ambulatory-care facilities will be encouraged to form collaborative groups.
• The deduction for employers who maintain prescription drug plans for Medicare Part D retirees will be eliminated.
• Medicare payroll taxes will increase (by several thousand dollars) for individuals and families making more than $200,000 and $250,000, respectively; investments income will also be taxed. The measures are expected to raise $53.8 billion.
• Hospitals meeting performance standards (eg, reduced Medicare spending per beneficiary) will receive value-based incentive payments, and Medicare reimbursements to hospitals with high rates of preventable readmissions will be reduced.

In the year 2015:

• An Independent Payment Advisory Board will be created to develop and propose ways to bolster the solvency of Medicare.
• A value-based (not volume-based) Medicare reimbursement program for physicians will be established.

In the year 2020:

• The doughnut hole in Medicare coverage for prescription drugs should be filled—meaning than recipients will pay a fraction of their drug costs until the catastrophic coverage level is reached.

* Privately run Medicare-approved health plans that provide prescription-drug coverage.

Image of 45 cover of Zager and Evans's no. 1 hit from Wikipedia. Both Zager and Evans qualified for Medicare 2 years ago. 

Recently detected DNA fragments of a common pig virus, circovirus type 1 (PCV1), in GSK's Rotarix vaccine have been present since the early development of the vaccine, says the FDA. The agency reported that GSK found the PCV1 DNA fragments in the "working cell bank" and viral "seed" that was used to produce the oral vaccine. Consequently the contaminated Rotarix vaccine was assessed in clinical studies, which were the basis for FDA approval. The detection of PCV1 DNA fragments does not necessarily mean that intact virus was or is present in the vaccine; moreover, the virus itself is not known to cause human disease.

How GSK learned of the presence of PCV1 DNA fragments in Rotarix is somewhat sketchy in detail. According to the FDA, an "independent US academic research team," while assessing a number of vaccines with a "new technology," detected the PCV1 DNA fragments. After finding the DNA fragments in 2 lots of Rotarix vaccine, the researchers alerted GSK on February 9th. Follow-up tests by the company confirmed the presence of the DNA fragments in the 2 tested lots, as well as samples leading back to the seed virus. GSK notified the FDA on March 10th, and the agency, as a precautionary measure, suspended the use of Rotarix yesterday.

The GSK press release provides 2 references on PCV1:

Li L, Kapoor A, Slikas B, et al. Multiple diverse circoviruses infect farm animals and are commonly found in human and chimpanzee feces. J Virol. 2010;84:1674-1682. (From the Blood Systems Research Institute in San Francisco.)

Hatterman K, Roedner C, Schmitt C, Finsterbusch T, Steinfeldt T, Mankertz A. Infection studies on human cell lines with porcine circovirus type 1 and porcine circovirus type 2. Xenotransplantation. 2004;11:284;294. (From the Robert Koch Institut in Berlin.)

Li et al used something called viral metagenomics to identify "circovirus-like" DNA sequences in stool samples of humans and wild chimpanzees. Viral metagenomics is apparently a relative new field, in which researchers attempt to recover viral DNA from environmental samples (as opposed to laboratory cell lines).* In US adults, the detection of circovirus was limited to the discovery of porcine circovirus (which is also found in most US pork products, according to the authors).

Hatterman et al reported on their infection of human cell lines with PCV1, which did not cause "any visible changes," unlike the type 2 PCV strain.

For children who require rotavirus vaccination, the FDA recommends the use of Merck's Rotateq vaccine—which is evidently not contaminated with PCV1 DNA.

* The technique may (may) be the method by which PCV1 DNA fragments were detected in GSK's Rotarix vaccine.

Image of Rotarix administration from Rotarix Prescribing Information.

03/26/10 addendum: Relying on reason and common sense, the European Medicines Agency reported today that it "sees no safety concerns with the Rotarix oral vaccine" and that the DNA of a virus that does not cause human disease "does not present a risk to public health." The EMA stressed that PCV1 is commonly found in meat and other food products.

The agency, however, requested that 1) GSK identify how the DNA fragments got into Rotarix and 2) produce a vaccine that is free of PCV1 DNA. The agency also reported that other GSK vaccines do not contain PCV1 DNA. 

Today: Addressing Friday's semi-interesting news while ignoring yesterday's monumental news.

Last week, the FDA released its warning about an increased risk of myopathy with high-dose simvastatin (Zocor; Merck). The warning is based on a review of preliminary safety data from the SEARCH trial and "other sources." The data show that, while the risk of myopathy is considerably higher with high-dose simvastatin (vs low-dose simvastatin), it is still relatively uncommon (<1%).

Risk	Simvastatin 80 mg/d (n = 6031)	Simvastatin 20 mg/d (n = 6033)
Myopathy	52 (0.9%)	1 (0.02%)
Rhabdomyolysis*	11 (0.02%)	0

The agency also reemphasized several warnings about the heightened risk of myopathy with simvastatin specifically and statins (or HMG CoA reductase inhibitors) generally. These warnings include the use of concomitant drugs that inhibit the CYP3A4 enzyme and thereby increase the concentrations of some statins—namely atorvastatin (Lipitor; Pfizer), lovastatin (Mevacor; Merck), and simvastatin.

In fact, statins have been recognized to increase with risk of myopathy and rhabdo (typically in a dose-dependent fashion) since the Dawn of Statins in the mid-1980s (beginning with Mevacor).** Yet, despite more than 20 years of clinical experience with statins (and squillions of dispensed prescriptions), we still don't know exactly how statins can cause myopathy.

The mystery necessitates a shortish, painful trip down Biochemistry Lane.

According to a literature review (see, for instance, here), the leading hypothesis implicates the statin-induced depletion of isoprenylated proteins that are products of the cholesterol-producing HMG CoA-reductase pathway. Depletion of these isoprenylated proteins, or isoprenoids, may lead to high levels of calcium in muscle cells, which activate mitochondria-triggered apotosis.

Now: Must read People magazine.

SEARCH = Study of the Effectiveness of Additional Reductions in Cholesterol and Homocysteine.

* Muscle breakdown with high creatine kinase (CK) levels (generally 10 or more times the upper limit of normal). The big risk with rhabdomyolosis is myoglobin-induced renal failure.

** Bayer's cerivastatin (Baycol) was famously recalled from the worldwide market in 2001 owing to an increased risk of rhabdomyolysis (especially when compared with other marketed statins). According to Law and Rudnicka, the incidence of statin-induced rhabdo (excluding Baycol-induced rhabdo), is 3.4 per 100,000 person-years of treatment; the fatality rate of rhabdo is about 10%.

Image of right quadriceps muscles from Gray's Anatomy (1918).

Born to Kill

(1947): There's something about a strapping, murderous sociopath that's simply irresistible. Must be the "strapping" part.

In this Robert Wise joint, San Francisco socialite Helen Brent (played by Claire Trevor, the undisputed Queen of Noir) appreciates more than physical attributes in the low-rent Sam Wild* (played by big, bad Lawrence Tierney). This homme fatale, who is to become (gasp!) Helen's brother-in-law, has got one helluva thrilling, rudderless soul.

Other than smoke like a chimney, what's a horny, morally conflicted gal to do?

Featuring exceptional supporting performances by Walter Slezak (an unctuous PI), Elisha Cook, Jr (Sam's officious sidekick), and Esther Howard (a beer-loving landlady). The DVD offers expert commentary from the ever-amusing and informative Eddie Muller and a few audio clips from the director himself.

N.B. While Ben Affleck may have a passing resemblance to Lawrence Tierney, at least as far as the movie poster is concerned, there is a world of difference between the two when it comes to screen presence.

* Wild. Get it? Get it?

The famous (or infamous) NEJM meta-analysis of rosiglitazone (Avandia; GSK) studies by Nissen and Wolski—who concluded that the drug increases the risk of MI—initiated a flood of articles in the medical literature, most of which were opinion pieces.* As logic would dictate, the authors of these articles either 1) favored the continued use of Avandia (denying that the drug increases MI risk); 2) recommended discontinuation of Avandia (stating that the drug increases MI risk); or 3) were neutral on the subject (stating that there is insufficient evidence to make a recommendation).

Given these widely differing opinions, physicians at the Mayo Clinic recently assessed these response articles to determine whether the opinions offered might be associated with the authors' relationships to pharma generally and the manufacturer of Avandia specifically. Their findings were reported yesterday in the BMJ.

What is most surprising in the Mayo assessment is the relative lack of disclosure among the 202 articles discovered. (Note: The authors excluded the many follow-up articles written by Nissen.) Only 108 (53%) provided a conflict of interest (COI) statement, despite the fact that all were published within the last 3 years (ie, during the burgeoning Age of Transparency). While 9 of 10 original research articles provided a COI statement, only 43% of the 91 letters, editorials, or commentaries and 59% of the 101 reviews, meta-analyses, or guidelines offered COI statements.

Consequently the Mayo physicians were obliged to search the Interweb for the remaining authors' potential COIs. They then determined that 90 (45%) articles were written by authors with COIs, but that only 69 (77%) of these articles provided a COI statement. In 3 articles, the authors declared no COI, but a web search revealed otherwise.

Among the 180 unique authors that were counted, the largest percentage (44%) were neutral on the subject of whether Avandia increases the risk of MI; 17% claimed no increased MI risk, and 36% concluded that Avandia increases the risk of MI. The COI breakdown is tabulated below.

COI	No MI Risk (n = 31)	Neutral (n = 84)	MI Risk (n = 65)
General, %	94	38	28
Avandia, %	87	24	20
Actos, %	65	30	22

The Mayo docs concluded that authors who came down on the side of no increased MI risk were significantly more likely to have relationships with pharma in general, the manufacturer of Avandia (GSK), and the manufacturer of Avandia's main competitor, pioglitazone (Actos; Takeda).

A similar pattern was discovered when considering whether authors recommended the continued use of Avandia.

COI	Favor Use (n = 26)	Neutral (n = 116)	Disfavor Use (n = 38)
General, %	88	40	26
Avandia, %	81	26	24
Actos, %	73	26	26

It is important to note that the possible influence of a pharma relationship wasn't limited to opinions on Avandia. Of the 29 articles that "strongly recommended" using Actos over Avandia, 86% were written by individuals who had a COI with the manufacturer of Actos.

Although the BMJ study is intriguing (in its narrowly focused sort of way), a big problem with it, in my mind, is that the authors failed to acknowledge the distinction between the COIs of pharma employees and those of academics.*** The former is expected (and expected to be highly influential), while the latter is the primary concern when it comes to preserving the integrity of the medical literature and mitigating any undue influence that pharma might have on medical practice. Unfortunately the BMJ authors neglected to make the distinction and stratify their assessments accordingly.

* The interim analysis of Home et al, which concluded no increased risk of MI with rosiglitazone use, also instigated its share of published responses, albeit it to a lesser extent than the meta-analysis by Nissen and Wolski.

** A direct competitor of Avandia. Actos actually has a cardiopotective effect, according to a randomized, controlled trial by Dormandy et al (2005).

*** Another big problem: Implicit within the study is that a relationship with pharma is necessarily a negative influence, rather than an indicator of greater knowledge of a drug's activity and associated clinical data.

In clinical practice, providing sedation to the "imminently dying" is distinguished from euthanasia. The former is intended to relieve suffering; but unlike euthanasia, it is not intended to hasten death. Whether neurologists understand this distinction and know or agree with the use of guideline-directed sedation for the imminently dying (SFTID) was explored in a survey of neurologists who have a specific interest in these types of ethical issues.* The results of the survey are available in an advanced online publication of the journal Neurology.

Among the 111 respondents, most were moderately (39.8%) or very (22.2%) familiar with the concept of SFTID, and the overwhelming majority agreed (51.8%) or strongly (44.5%) agreed that the practice is intended to relieve suffering. A large majority also correctly disagreed with the ideas that SFTID is intended to hasten death and is the moral or legal equivalent of euthanasia.

When presented with 5 case scenarios, respondents were much more likely to use SFTID in patients with terminal metastatic cancer (92%) than in patients with end-stage ALS (50%). Only a small percentage (7%) agreed that SFTID was acceptable in a case of traumatic quadriplegia.

Actual experience with SFTID was spotty. Nearly 50% of respondents said that SFTID was administered under the guidance of an institutional policy. About 13% reported that it was practiced covertly. Ten percent said that SFTID was not practiced at their institution, and approximately 30% were unsure.

Despite the inconsistent experience with SFTID, demand for the procedure appeared to be relatively high. A little more than half of the respondents reported that they had been asked to provide SFTID; however, 58% said they would prescribe SFTID only if an institutional policy supported its use.

With respect to the reluctant use of SFTID in end-stage ALS, the survey results suggest that respondents either disagree with or are unaware of the 14-year-old AAN position statement on palliative care. The authors also imply that some respondents may be under the impression that ALS patients do not experience physical pain or discomfort, despite evidence to the contrary. Equivocal end-of life recommendations from a more recent AAN Practice Parameter for ALS (see here and here) are also a likely source of confusion for practitioners.

* Voluntary members of the Ethics Section of the American Academy of Neurology.

Image of sleeping Buddha from h.koppdelaney at Flickr. 

This week, the ACC, as an arena for impassioned conflict, didn't stand solely for the Atlantic Coast Conference. A heated confrontation also occurred at the annual meeting of the American College of Cardiology, where Duke physician Robert Harrington debated the Cleveland Clinic's attention-loving Steve Nissen on the issue of physicians' relationships with industry.

Both cardiologists acknowledged historical examples of the marketing influence that pharma and the medical-device industry have had on professional education and, potentially, medical practice. But Harrington painted a more complex picture, in which physicians and medical journal publishers have been complicit in allowing this influence to happen. While Harrington advocated that ongoing relationships with commercial entities are "critical," he urged clear "firewalls" between physicians (particularly academic physicians) and industry and full access to data from industry-funded research. Harrington also correctly stressed that potential conflicts of interest go beyond money; "scientific hubris" is also in the mix.

And speaking of hubris...

Nissen conversely argued that industry funding to sponsors of continuing medical education (CME) and professional medical societies must cease. He cited a Merck-funded CME program at the ACC's Cardiosource web site, "Optimizing Patient Outcomes in Acute Heart Failure Syndromes: Strategies to Preserve Cardiorenal Function," which was sponsored by an accredited* medical-education communications company (Med-IQ) and the ACC.** Without citing specific examples of undue industry influence in the program, Nissen argued that Merck's reason for sponsoring the program was due to the fact that the company had a novel compound, rolofylline, in development that addressed the condition in question. Nissen called the CME program a "market preparation business activity" and an ultimate "misuse of medical information," primarily because the drug died in phase 3 development. But Nissen failed to acknowledge the obvious follow-up question: How could Merck influence cardiac practice with this particular CME program if rolofylline can never be prescribed?

Using an even more tenuous example, Nissen implied that the American Heart Association had backed away from a study that linked soft-drink consumption with cardiac risk factors and an NEJM-advocated soft-drink tax, on the basis of the AHA's alleged marketing relationship with Coca-Cola. As evidence, Nissen offered up the red-dress logo for The Heart Truth educational campaign, which has been prominently displayed on cans of Diet Coke. Nissed charged that the logo comes from the AHA.

However, on this very circumstantial point, Nissen appears to be wrong in his facts. According to MedPage Today, the logo belongs to the National Heart, Lung, and Blood Institute. Moreover, both the AHA and the NHLBI deny that any money has been exchanged between Coca-Cola and their organizations to produce the campaign. The Heart Truth program is solely funded by government entities, according to an NHLBI spokesperson.

Those physicians who argue that ties between industry and medical practice should be severed may have some valid points, but Steve Nissen didn't deliver their perspective in any compelling fashion in this debate. Like in the recent b-ball champ-ship, the hands-down ACC winner here was (the guy from) Duke.

N.B.--Audio portions of the debate are provided by MedPage Today.

* Nissen called the Accreditation Council for CME, the organization that accredits other organizations to sponsor certified CME, "absolutely pathetic" and a "toothless watchdog."

** Notably the program included faculty from Duke (acknowledged by Nissen) and the Cleveland Clinic (not acknowledged by Nissen).

Image of The Heart Truth campaign logo from the NHLBI web site.

Addendum: The AHA sponsors the trademarked Go Red for Women campaign, which is supported by Macy's and Merck, according to the campaign web site. The campaign's logo (left), while incorporating a red dress, is distinct from The Heart Truth's logo. Both red-dress logos are trademarked by the DHHS.

03/19/10 addendum: Christopher Cannon, Harvard cardiologist and Cardiosource Editor-in-Chief, reviewed the Merck-sponsored CME program that was criticized by Dr. Nissen and provided a lengthy comment at MedPage Today. Among 5 talks, according to Cannon, 4 did not mention Merck's (now defunct) drug in development, rolofylline. The talks covered the pathophysiology and epidemiology of the condition in question, possible interventions, and clinical development. Last a case was presented "where the drug is not mentioned." Cannon counted 130 slides in the CME program, 8 (6%) of which concerned the funder's drug in development. Cannon concluded, "This is I believe a fair balanced program and it does not meet the charaterization [sic] stated by Dr. Nissen." 

Hospitalizations are reduced by the upfront use of a genetic test for "warfarin sensitivity," according to new results from a comparative-effectiveness study. The Medco- and Mayo-sponsored trial of the anticoagulant (the dosing of which has caused more than one headache in physicians and patients during the last 70 years) compared hospitalization rates among warfarin-treated subjects who underwent genetic testing and those who didn't. The trial results were presented this morning at the ongoing meeting of the American College of Cardiology in Atlanta; data are also available at the company's web site.

In the study, the dose of newly initiated warfarin therapy in nearly 900 adult patients* was adjusted on the basis of Medco's genetic test (performed on blood or cheek swabs). During a 6-month period, the hospitalization rate in this group was 31% lower than that of a historical control group (N = 2688) who had not undergone genetic testing (ITT analysis: ~18% vs ~25%). The hospitalization rate for bleeding or thromboembolism was 28% lower in the genotyped group.

Results from the per-protocol analysis were even more impressive. The rate of all-cause hospitalization and the rate of hospitalization for bleeding or thromboembolism were 33% and 43% lower, respectively, in the genotyped group.

The genetic test, which is available from several companies,** assesses the function of 2 genes, CYP2DC and VKORC1. The former encodes a well-known P450 enzyme that metabolizes warfarin; the latter encodes an enzyme that activates vitamin K (which counteracts the anticoagulant properties of warfarin). The cost of a warfarin sensitivity test is quoted in the press at a range of $250-$400. The FDA first approved use of the genetic test (Verigene; Nanosphere) to inform warfarin dosing in 2007.

According to Medco, about 30 million warfarin prescriptions are written and 2 million patients start warfarin treatment each year. Warfarin is the leading cause of ED visits, hospitalizations, and drug-related deaths. One third of the variability in response to the drug is ascribed to the genetically determined function of CYP2C9 and VKORC1.

Last week, the FDA added a boxed warning to the PI for the antiplatelet drug clopidogrel (Plavix; BMS/sanofi), which may be less effective in patients with reduced function of the CYP2C19 enzyme. (To become active, clopidogrel, a prodrug, must be converted by CYP2C19.) The FDA advised that 2%-14% of Americans are "poor metabolizers" of clopidogrel. CYP2C19 testing is also commercially available through a number of companies.

ITT = intent to treat; PI = package insert.

* Patients were recruited through 29 Medco-managed prescription benefit plans.

** For example, Ambry Diagnostics and Arup Laboratories.

Image of warfarin (Coumadin) bottles from NIGMS/NIH.

As just about everyone knows by now, the Special Masters of the US Court of Federal Claims handed down their decisions on Friday, which deny a causative link between the vaccine preservative thimerosal and autism in 3 test cases.

Among the many opinions rendered in the decisions from the Special Masters (see here, here, and here) are discussions of the autism studies published by Mark and David Geier—whose work has been criticized sharply and at length at this blog and in my 2009 letter to the Journal of the Neurological Sciences.

The court's Special Master George Hastings, for instance, writes in his decision re King v Secretary of Health and Human Services: 

[M]ost of the epidemiologic studies that have addressed the thimerosal/autism causation issue have failed to find any association between thimerosal-containing vaccines and autism, but there have been certain exceptions. Those exceptions were studies published by the research team of Dr. Mark Geier and his son David Geier[*]...To be sure, the petitioners in this case have not cited or relied upon those Geier studies in their post-hearing briefs, because, as I will discuss below...the petitioners argue that all of the epidemiologic studies done to date are irrelevant to the petitioners' causation theory in this case. However, since I find that the epidemiologic studies are of relevance, I have found it reasonable to examine those Geier studies, to see if they afford any significant counterweight to the many contrary studies...

After careful consideration, I conclude that the Geiers' studies cannot be given any weight. A number of those studies were considered by the Institute of Medicine (IOM) committee that fully studied the entire thimerosal/autism causation issue in 2004. That committee concluded that the studies were so flawed as to be "uninterpretable," and that the studies contributed nothing meaningful ("noncontributory") concerning the causation issue...The committee noted that the studies were based on databases that themselves had "significant limitations"...and that the studies had "serious methodological problems"...or "serious methodological limitations"...The committee added that the Geiers' articles describing their analytical methods were "not transparent" and omitted "important details," so that it was impossible to evaluate the studies...Other specific deficiencies in the studies were also discussed, including the fact that the Geiers incorrectly used several epidemiologic terms and measures. 

In addition, Dr. Fombonne [respondent's expert] agreed with the IOM's criticisms of the Geier studies, and testified that the Geier studies in general failed to use accepted epidemiologic methods...Dr. Rutter [respondent's expert] was critical of the Geier studies as well...Further, petitioners' own expert witness concerning epidemiology, Dr. Greenland, agreed with the criticisms of the Geier articles, acknowledging that those studies are "deficient in methodology"...And none of the expert witnesses for the petitioners vouched for the reliability of the Geier studies.

I have reviewed the published Geier studies discussed in the 2004 IOM report, and I agree with the analysis of those studies set forth in that IOM report. Further, I have reviewed the additional studies published by the Geiers since the 2004 IOM report, and find that those studies suffer from the same type of flaws as the earlier Geier studies. That view includes a study published in 2008 by the Geiers, along with Young as the third author. Two of  respondent's experts, Drs. Fombonne and Rutter, testified that that 2008 study was again deeply flawed, and those experts provided a number of specific examples of deficiencies in the study...And, again, none of the petitioners' experts testified in support of that 2008 Young, Geier, and Geier study.

In summary, I conclude that all of the Geier epidemiologic studies are not reliable, and cannot be accorded any weight.

In a lengthy footnote from the decision handed down in the case of Mead v Secretary of HHS, Special Master Patricia Campbell-Smith writes,

Although the studies conducted by Dr. Mark Geier and his son purport to find an association between thimerosal-containing vaccines and autism, their studies have been criticized consistently by various reviewers, including petitioners' own expert epidemiologist, as methodologically deficient...(Dr. Rutter [characterized] the 2008 Young study—that was conducted in part by Dr. Geier and his son...as a poorly designed study for the following reasons: (1) the researchers used a "strange" study design that is both a cohort study [a controlled study] and a time-trend analysis of the available database information [an ecological study] and (2) the researchers included emotional disturbance as one of the neurodevelopmental disorders observed following exposure to thimerosal-containing vaccines even though emotional disorders are not included in any of the official psychiatric classifications systems for neurodevelopmental disorders). The undersigned has reviewed carefully the presented studies conducted by the Geiers and has considered the criticisms leveled against the Geiers' studies. Persuaded that the studies are flawed methodologically in critical respects, the undersigned, without addressing the studies in extensive detail here, declines to accord any evidentiary weight to the studies. The undersigned notes that other researchers have been unable to verify the validity of the Geiers' statistical analysis on a number of occasions and a number of courts have expressed concerns about the reliability of their work.

Campbell-Smith goes on to cite 8 court cases in which the Geiers' work was called, among other things, "unintelligible," or in which Dr. Geier's testimony was described as "not reliable."

In her decision for the third test case, Special Master Denise Vowell affords special attention to the Young, Geier, and Geier study of 2008—which was specifically pulled apart at this blog and by Epi Wonk.

The only studies demonstrating a relationship between TCVs [thimerosal-containing vaccines] and ASD [autism spectrum disorder] are those in which Dr. and Mr. Geier appear as co-authors, including the Young study published in May, 2008, and funded by the OAP PSC [Omnibus Autism Proceeding Petitioners' Steering Committee]...Because petitioners’ own expert commented that the Geier studies were not reliable as evidence... and they were thus not addressed by respondent’s experts, I do not discuss the earlier Geier studies any further. In view of the numerous criticisms of the earlier Geier studies and petitioners' own expert’s dismissal of them, I have placed no reliance on them.

The Young study was an ecological analysis using the VSD database...Doctor Greenland [petitioners' expert] did not comment on this study during his testimony, as the article was introduced after his appearance and excusal. The study found an increased risk of ASD, based on increasing exposure to TCVs. Doctor Fombonne offered several criticisms of this study. In a critique common to many of the studies performed by Dr. and Mr. Geier, Dr. Fombonne commented that the Young article did not provide the data that would allow others to verify the calculations performed.

Doctor Fombonne reproduced one chart from the article...Using the chart, he explained that the birth cohorts used in the study did not all contain the same number of individuals, with most representing 40,000 children...One birth cohort, that of children born in 1990, contains only 2,000 children...When this "outlier" is removed, the purported statistical relationship between ASD and TCVs during the first four years of the sample disappears.

Doctor Fombonne was also highly critical of the authors' addition of invented numbers to the 1995 and 1996 data from the VSD...If the adjustments are removed, there is no correlation at all between the increase in thimerosal exposure and increase in autism cases per 10,000...Doctor Fombonne commented: "It’s dishonest to impute like 45 new cases which are just invented to top up the prevalence in a way which is supportive of their hypothesis. It’s clear that these investigators have a clear track record to do with the data that supports their hypothesis. And I’ve seen that in their previous papers."

Doctor Rutter offered similar criticisms of the Young study...calling it "a poor study for several different reasons"...It began with a cohort design, but ended up being analyzed as a time trend study. That required the authors to make adjustments to the first and last cohorts. Doctor Rutter described this as "putting together chalk and cheese in the hope of gazpacho soup coming out"...The "analytic design and strategy was not a satisfactory one."

He pointed to Table 3 as a striking example of the poor design...Table 3 compares "neurodevelopmental disorders" to several control disorders, measuring the difference in rates of the disorder developing in the cohorts that received 100 micrograms more mercury. The table shows higher rate ratios for autism, ASD, ADD/ADHD, developmental or learning disorders, disturbance of emotions, and tics...Doctor Rutter called this table an example of demonstrating a statistical effect without showing a causal effect...If the neuroinflammation hypothesis is correct, it is difficult to explain how neuroinflammation causes tics or disturbance of emotions. The study reported TCV effects across a very broad range of unconnected disorders having different ages of onset, different genetic factors, and different disease courses...The broad range of effects in these diverse disorders caused Dr. Rutter to be "immediately skeptical as to what [the study] shows."

He also questioned why "disturbance of emotions" was listed in the category of neurodevelopmental disorders, noting that anyone knowledgeable about the field of neurodevelopmental disorders would not have categorized it as one, and would have placed it with the control disorders...To prove their hypothesis that increased mercury exposure causes increases in neurodevelopmental disorders but not control disorders, the authors have to demonstrate that mercury is associated with increased rates of one but not the other. If "disturbance of emotions" was properly placed with the list of control disorders, it would undercut the authors' hypothesis. Their comparison between the two groups is therefore invalid.

Vowell also comments on a reanalysis of the Young et al data by Young herself, who found no association between birth year (which was purported to be associated with exposure to TCVs) and ASD when the imputed cases were removed.

Doctor Young’s subsequently-filed letter indicated that she reanalyzed the data to respond to Dr. Fombonne's criticisms. After she removed the 1990 birth cohort (the one containing only 2,000 cases) and the notional cases for 1995 and 1996, the results for autism, ASD, and unspecified developmental disorders lost statistical significance...She nevertheless defended the use of the 1990 birth cohort and her adjustments to the numbers for 1995 and 1996.

Vowell also dismisses the study of Young et al on the basis of its funding source.

For the reasons indicated in the criticisms proffered by Drs. Fombonne and Rutter, I have accorded the Young study little weight. An additional reason for viewing this study as unreliable is the conflict of interest generated by the PSC’s funding of the study. In its opinion on remand in Daubert, the Ninth Circuit considered whether the matters an expert proposed to testify about flowed from research conducted independently of involvement in the litigation in question, noting that this factor provides objective proof that the research was conducted for scientific purposes.

Yet, despite these unequivocal, disparaging opinions on the work of Geier and Geier, they continue to find sympathetic medical publishers. Their latest article (pdf here) can be found in the Journal of Toxicology and Environmental Health, Part A, which has now published the Geiers' work on 5 occasions.

In their latest article, the Geiers (along with Janet Kern of the Genetic Consultants of Dallas) again try to link the excretion of some urinary porphyrins (their dubious pet marker for mercury toxicity) with ASD severity. The study is very similar to their previously published work in the JNS, and one wonders if there isn't substantial overlap in the study subjects (26 vs 28 children).

Despite the suspicion, the tabulated presentation of the Geiers' urinary porphyrin data in JNS (nanomoles per gram of creatinine) makes it virtually impossible to compare these numbers with their urinary porphyrin values in the latest article (which are presented in "normalized" uP levels). Similar objections can be raised of their graphed data, primarily because of differences in the presentations of the x-axes.

N.B.--The Geier studies reviewed by Special Master Hastings included the following:

Geier DA, Geier MR. An assessment of the impact of thimerosal on childhood neurodevelopmental disorders. Pediatr Rehabil. 2003;6:97-102.

Geier DA, Geier MR. A comparative evaluation of the effects of MMR immunization and mercury doses from thimerosal-containing childhood vaccines on the population prevalence of autism. Med Sci Monit. 2004;10:P133-P139.

Geier DA, Geier MR. A two-phased population epidemiological study of the safety of thimerosal-containing vaccines: a follow-up analysis. Med Sci Monit. 2005;11:CR160-CR170.

Geier DA, Geier MR. An evaluation of the effects of thimerosal on neurodevelopmental disorder reported following DTP and Hib vaccines in comparison to DTPH vaccine in the United States. J Toxicol Environ Health A. 2006;69:1481-1495.

Geier DA, Geier MR. An Assessment of downward trends in neurodevelopmental disorders in the United States following removal of thimerosal from childhood vaccines. Med Sci Monit. 2006;12:CR231-CR239.

Geier DA, Geier MR. A meta-anlysis epidemiological assessment of neurodevelopmental disorders following vaccines administered from 1994 through 2000 inthe United States. Neuro Endocrinol Lett. 2006;27:401-413.

Geier DA, Geier MR. A case series of children with apparent mercury toxic encephalopathies manifesting with clinical symptoms of regressive autistic disorders. J Toxicol Environ Health A. 2007;70:837-851.

Geier DA, Geier MR. A prospective assessment of porphyrins in autistic disorders: a potential marker for heavy metal exposure. Neurotox Res. 2006;10:57-64.

Geier MR, Geier DA. Thimerosal in childhood vaccines, neurodevelopment disorders, and heart disease in the United States. J Am Phys Surg. 2003;8:6-11.

Geier MR, Geier DA. Neurodevelopmental disorders after thimerosal-containing vaccines: a brief communication. Exp Biol Med (Maywood). 2003;228:660-664.

On the basis of his success with The Manchurian Candidate (1962), director John Frankenheimer was able to assemble a similar behind-the scenes crew for another B&W political thriller, Seven Days in May (1964). This time, however, Rod Serling (not George Axelrod) penned the highly effective screenplay.

The movie, based on a popular novel of the same name, is the story of an attempted military coup in the United States, spearheaded by the head of the Joint Chiefs of Staff (Burt Lancaster). The planned coup is in response to a nuclear disarmament treaty signed by an unpopular President (Fredric March). Kirk Douglas plays Lancaster's right-hand military man, who alerts the Administration to his boss's overthrow plot.

The soul-searching dialog, as noted by Frankenheimer in the DVD commentary, is pure Serling:

General Scott (Lancaster): You're a night crawler, Colonel. A peddler. You sell information. Are you sufficiently up on your Bible to know who Judas was?

Colonel Casey (Douglas): I suggest you read that letter, sir. It's from the President.

General Scott: I asked you a question.

Colonel Casey (hesitantly): Are you ordering me to answer, sir?

General Scott (angrily): I am!

Colonel Casey (calmy, stoically): Yes, I know who Judas was. He was a man I worked for and admired...until he disgraced the four stars on his uniform.

Thanks to a new editorial at the Archives of Internal Medicine web site, much is being made of the high-end technology that was used to recently examine POTOS's health status. At issue, according to cardiologist Rita Redberg, the journal's editor, is the ill-advised use of 2 noninvasive screening tests—electron-beam CT (EBCT) to look for coronary calcium (a marker of coronary heart disease) and virtual colonoscopy to look for colon cancer. Redberg argued that both tests unnecessarily exposed POTOS to radiation, which increases his risk of cancer. Moreover, she maintained, their use in the President stands as a hallmark of what's wrong with the US's expensive test-heavy health care.

With respect to the criticism of screening EBCT, Redberg cited Kim et al, who estimated that the lifetime radiation-induced incidence of cancer from a single EBCT scan in a 55-year-old man is 8 per 100,000 persons. (Most of the increased cancer risk is due to an increased risk of lung cancer [6 per 100,000 persons].)* Redberg further argued that the radiation-induced cancer risk of EBCT does not outweigh the benefit of this test in low-risk persons, like POTOS. To support this contention, she cited the 2004 recommendation of the US Preventive Services Task Force, which advised against screening for coronary heart disease with resting ECG, an exercise treadmill test, or EBCT in low-risk persons.

What isn't crystal clear, however, from the USPSTF recommendation is what constitutes a low-risk person. It is generally assumed to be someone with a less-than-10% risk of MI during the next 10 years. However, it is worthy to consider whether a less-than-10% MI risk should be parsed further when the patient in question is POTOS.

Obama's risky smoking habit, the depth of which is unclear, is otherwise well known. Assuming that the President is not taking antihypertensive medication, his 10-year risk of heart attack is 7%, according to the online formula provided by the National Cholesterol Education Program. If Obama didn't smoke, his 10-year MI risk would be 3% (Plugged-in values for the online formula were taken from an AP report on President Obama's health status.)

Now: Is a 10-year MI risk of 7% low, if we're talking about the President, and Joe Biden's next in line? And Nancy Pelosi after that? While nobody's maintaining that Obama's smoking habit should take a back seat in relevance to his coronary calcium score (via EBCT), the latter information is debatably important in someone whose health affects many, many (did I stress many?) people. 

The issue is not that Obama deserves superior health care, which screening EBCT evidently doesn't provide (at least on a population level, circa 2004), because he is the President; the issue is that extra measures can arguably be taken to obtain more information specifically on Obama's cardiac health, given that he is a smoker and POTOS. 

Redberg also implicitly chastised POTOS's physician for ordering a virtual colonoscopy to screen for colon cancer, "even though this screening is not recommended in [Obama's] age group." Redberg again cited the USPSTF, which recommended screening for colon cancer at the age of 50 years (Obama is 48) with fecal occult blood testing, sigmoidoscopy, or colonoscopy. (You talk to most physicians, and they'll generally recommend screening colonoscopy, beginning at the age of 50 years.)

Redberg noted that the USPSTF does not recommend virtual colonoscopy for screening purposes, because of 1) a lack of supportive evidence to justify its use (again, on a population level, this time circa 2008) and 2) the unnecessary exposure to potentially cancer-inducing radiation (like with EBCT).

However, in an AP article from today, the White House countermanded Redberg by stating that earlier screening for colon cancer is sometimes recommended in high-risk groups like African Americans.** Further, the advantage of virtual colonoscopy over conventional colonoscopy is that the former doesn't require sedation, which might necessitate a transfer of Presidential power to [shudder] Joe Biden.

N.B.--It is assumed that virtual colonoscopy was performed on the President by means of CT, rather than MR. Unfortunately virtual colonoscopy, like conventional colonoscopy, requires colon preparation (and for anybody who's undergone a colonoscopy, the 24-hour prep is the decidedly unpleasant part).

* Kim et al also noted that the radiation exposure during EBCT varies widely.

** POTOS is black.

Reconstructed CT images of a colon (not Obama's) from the National Cancer Institute.

Yesterday the Senate passed another bill to postpone the mandated 21% reduction in Medicare reimbursement to physicians. The $140-million bill, passed by majority Democrats,* delays the draconian Medicare cut to October 1st and also extends unemployment benefits, COBRA subsidies, and state funding through the American Recovery and Reinvestment Act of 2009. Dissenting Republican Senators, like Jeff Sessions (AL), argue that the bill adds $100 billion to the federal deficit. The bill will now be passed on to the House for a vote.

Most recently, Republican Senator Jim Bunning (KY) stalled a bandaid bill that delayed the SGR-defined cut in Medicare reimbursement to April 1st. On March 3rd, Bunning finally relented on a vote, and the bill was immediately signed into law.

According to Medscape, this is the third time in 4 months that Congress has acted to delay the cut in the Medicare reimbursement rate. The repeated passage of stop-gap bills has been characterized by critics as "kicking the can down the road." It is hoped that the latest bill, if enacted, will allow Congress enough time to create a permanent fix to the perpetually looming drop in Medicare reimbursement.

COBRA = Consolidated Omnibus Budget Reconciliation Act; SGR = sustainable growth rate.

* In a 62-to-36 vote.

Photo of weathered can from magannie at Flickr.

Addendum: Over at MedPage Today, a poll ("How would a delay in SGR cuts without higher reimbursement rates affect your Medicare practice?") reveals that about about a third of physician respondents would continue to accept new Medicare patients, a third would refuse to accept new Medicare patients, and the remaining are not sure.

Yesterday the FDA approved Botox (onabotulinumtoxin A; Allergan) to treat distal arm spasticity in adults.* The approval was based on results from at least 3 trials in a total of 305 people with arm spasticity after stroke. Two of the 3 studies have been published in peer-reviewed journals (see here and here).

While the FDA's new approval partially mitigates the legal issue that Allergan has had with the agency's mandate to disseminate off-label safety information about Botox (for necessary background, go here, here, here, and here), it does not resolve the problem with respect to the use of Botox for limb spasticity in children—a still unapproved indication.

The case of Allergan v the United States of America et al was scheduled for a motion hearing in the US District Court for the District of Columbia on March 2nd. However, the docket has evidently been altered. According to the current court calendar, a status conference is scheduled for March 25th in the chambers of Judge John D. Bates, and a motion hearing is scheduled for April 26th.

* Specifically the flexor muscles of the elbow (eg, biceps), wrist (eg, flexor carpi radialis), and fingers (eg, flexor digitorum profundus).

Image of deep muscles of the ventral forearm from Gray's Anatomy (1918).

The Alzheimer's Association has a new report on the large and growing effect of Alzheimer disease and other dementias on Americans. Here's the distillation:

• AD is the most common cause of dementia, affecting 5.3 million Americans (1.7% of the current US population). The vast majority (96%) of those affected are older than 64 years of age.
• Dementia affects women preferentially because they live longer, on average, than men. (Advancing age is the biggest risk factor for AD.)
• In 2006, AD was the 7th leading cause of death among all Americans. In those older than 64 years of age, AD was the 5th most likely cause of death.
• Next year, the first baby boomers will turn 65. In 30 years, all of the estimated 70 million baby boomers will be older than 65. The Association estimates that there will be 1 million new cases of AD by the year 2050.
• People with AD and other types of dementia need a lot of health care, including long-term and hospice care. In 2010, care costs for people with dementia will reach $172 billion. Medicare costs for people with dementia are nearly 3 times higher than those for the nondemented elderly. Medicaid costs are nearly 9 times higher. (Blogger's note: I suspect this is the result of Medicaid-funded nursing home care.)
• Older African Americans and Hispanics are about 2 and 1.5 times more likely, respectively, to have AD and other types of dementia than older whites.* Reasons for the higher risk of AD among these minorities include a greater prevalence of known risk factors for dementia, like hypertension, diabetes, and lower education and income levels. (Ethnically dependent genetic risks have not been identified.) Despite the higher risk of dementia among African Americans and Hispanics, the diagnosis is more likely to be delayed in affected minority patients. Delays in diagnosis mean missed opportunities for treatment, which is more likely to be effective in the early stages of AD.
• Last year, nearly 11 million family members or other uncompensated persons provided 12.5 billion hours of care for people with dementia. Unpaid care was assessed at $144 billion, which is more than the US government (ie, Medicare and Medicaid) spends on people with dementia. Costs of giving care are also measured in emotional and physical stress, declining caregiver health, and lost employment-related productivity. 

* This is the lead of today's press release from the Alzheimer's Association.

Photograph of atrophied brain from person with AD: National Institute on Alcohol Abuse and Alcoholism.

Trials of the monoclonal antibody ocrelizumab, a humanized version of the uber-mAb rituximab (Rituxan; Genentech/Biogen Idec), in rheumatoid arthritis and lupus have been halted because of drug-related infections and deaths. News of the grave snag in the mAb's phase 3 development (which is evidently not a huge surprise to those in the know) was announced today by the companies and reported in The Street and the WSJ. The study of ocrelizumab in multiple sclerosis, now in the phase 2 stage, continues.

Because profits from ocrelizumab would have been split 70-30, in Genentech's favor, the stalled development actually benefits Biogen Idec to some extent—because the company receives a greater share (40%) of the profits from Rituxan.* (Approval of ocrelizumab for RA, lupus, and any other condition would have eaten into Rituxan sales. A humanized mAb—meaning one that contains fewer mouse parts—is theoretically safer and provides greater long-term efficacy than a chimeric mAb, like Rituxan.)

Share prices of Roche, Genentech's owner,** are largely flat, while Biogen's stock price has climbed steadily since November for reasons that are unclear (to me). Biogen also sells the mAb natalizumab (Tysabri) and an IM version of interferon beta-1a (Avonex), both of which are FDA approved for the treatment of MS.

* An

arbitration ruling over the decision-making rights for the development of ocrelizumab and Rituxan was handed down in June of last year. Net US sales of Rituxan in 2008 totaled nearly $2.6 billion. Rituxan is currently FDA approved to treat non-Hodgkin's lymphoma, chronic lymphocytic leukemia, and RA.

** For those emerging from long-term unconsciousness: Last year, Roche bought Genentech for $46.8 billion USD.

Image of Son of Superman comic book cover from Wikipedia.

Raw Deal (1948): Underappreciated noir from director Anthony Mann,* with moody voiceover narration from Claire Trevor, the Queen of Noir. A northern California setting provides the fog.

The story: Homme fatale Joe (Dennis O'Keefe) takes the prison rap for a crime boss, Rick (Raymond Burr), who owes Joe 50 Gs. Rick then sets up a prison escape for Joe, while relying on the odds that he'll get caught. But Joe escapes the police dragnet with the aid of his lovesick BFF (Trevor) and the reluctant cover of a pretty legal aid.

Despite the caliber of the film, the transfer to DVD (Classic Media) provides the bare minimum. Not even a subtitle option to catch every last drop of juicy screenplay—let alone any deserving commentary.

* Of noir and western fame.

Pharma's financial layout in 2009 for DTC ads remained, for all practical purposes, stable, when compared with 2008's numbers. According to the latest Nielson data, by way of MM&M, a total of $4.5 billion was shelled out by drug companies for ads on TV (64%), in magazines (28%), in newspapers (4%), on the web (3%), and on the radio (1%).

Here's Ye Microsofte Pie for the graphically impressed (dollar amounts are in millions).

The identifiable trends for 2009 were increased spending on web ads (up 31%), cable TV ads (up 17%), newspaper ads (up 11%), and radio ads (more than doubled). Spending on Spanish-language media more than tripled.

For those who blame DTC advertising on the high cost of healthcare generally and that of drugs specifically, keep in mind that changes in DTC spending don't parallel the ever-increasing costs for drugs, outpatient care, and inpatient care.

Also costs for prescription drugs account for only about 12% of the overall healthcare spend (and are arguably one of the most cost-effective aspects of healthcare). In 2006, the spend on outpatient care was $850 billion (~41% of overall costs), and that on inpatient care was $458 billion (~22%), according to the McKinsey Global Institute.

Last year, the Congressional Budget Office reminded us that pharma invests relatively heavily in sales-rep detailing: $12 billion in 2008. The CBO's number for DTC ad spending in 2008 was $4.7 billion.

HT for lead: Pharmalot

The most common, identifiable form of pediatric epilepsy, absence seizures (formerly known as petit mal seizures) were first described in the early 18th century by (you guessed it) a French guy. Effective and relatively safe pharmacologic treatment for the condition has been available since 1960, when ethosuximide (Zarontin) was introduced by Parke-Davis (now a subsidiary of Pfizer, like just about every other drug company).

Absence seizures are also responsive to valproic acid (aka Depakene or Depakote; Abbott), which was FDA approved for treatment of the disorder in 1978, and lamotrigine (Lamictal; GSK), which has been studied for the treatment of absence seizures since at least the late 1990s.*

Despite our extensive clinical experience with these drugs, it was unknown which provided the best empirical therapy for absence epilepsy. In fact, Glauser and other neurologists at the University of Cincinnati concluded in 2006 that it was "impossible to develop an evidence-based guideline" for the initial, monotherapy treatment of generalized seizures and specifically those in children, because of the "alarming lack of well-designed, properly conducted" randomized, controlled trials. This finding evidently prompted Glauser and his colleagues to conduct a randomized, double-blind multicenter trial of the 3 drugs in children with newly diagnosed absence seizures—the results of which are available in today's issue of the NEJM.

Among 453 children with new-onset absence epilepsy, Glauser et al found that ethosuximide or valproic acid were significantly more likely to result in a primary composite outcome of seizure control and tolerability (~50%-60% of patients) than lamotrigine (~30% of patients) after 4 months. Attentional deficit, a secondary outcome measure, was significantly more likely with valproic acid than ethosuximide (49% vs 33%).

Commenting at MedPage Today, Glauser said, "[E]thosuximide gave the child the best chance to get the combination of seizure control without side effects or [adverse] effects on attention."

So ethosuximide, it is; then valproic acid; then lamotrigine.

* Although lamotrigine is not FDA approved for the treatment of absence seizures specifically.

The characteristic 3-per-second spike-and-wave EEG pattern of absence epilepsy from An Introduction to Epilepsy.

Someday I'm going to learn to capitalize on the overblown expectations and inevitable letdown of AD drug development.

Dimebon (latrepirdine), the nonselective antihistamine that Pfizer shelled out millions for, failed to improve cognition or global functioning in a placebo-controlled phase 3 study of patients with mild-moderate Alzheimer disease. The disappointing results were distributed today by way of press release from the drug's codevelopers, Medivation and Pfizer.

In a double-blind study of 598 individuals with AD in North America, Europe, or South America, Dimebon 20 mg tid was no better than placebo for improving or delaying declines in cognition (as measured with the ADAS-cog) or global functioning (as measured with the CIBIC-plus) at 6 months. Measures of secondary endpoints (eg, activities of daily living) were, likewise, similar between Dimebon- and placebo-treated patients.

As expected, the most frequently reported adverse events with the antihistamine were somnolence and dry mouth. A 5-mg treatment arm and another, large phase 3 safety study revealed consistent drug tolerability. For what it's worth, the phase 3 safety study showed that the drug can be taken with common AD medications, like cholinesterase inhibitors (eg, Aricept; Pfizer) or memantine (Namenda; Forest).

Results from the phase 3 efficacy study were to be used in conjunction with positive results from a phase 2 Russian study to support FDA approval. But, evidently, no more. 

In 2008, Pfizer agreed to pay Medivation $225 million upfront and another $500 million when the drug was approved. The agreement also conferred licensing rights to Pfizer for use of the drug in Huntington disease. Last month, results from a 90-day safety trial of Dimebon in HD showed that the drug may improve cognition.

The price of Medivation stock dropped nearly 30 points on release of the phase 3 trial results, from $40.12 to $12.88.

ADAS-cog = Alzheimer's Disease Assessment Scale-cognitive subscale; CIBIC-plus = Clinician's Interview-Based Impression of Change Plus Caregiver Input.

Photograph: Atrophied brain from person with AD from National Institute on Alcohol Abuse and Alcoholism.

Senator Bunning (R-KY) remains steadfast in his one-person crusade to block the passage of a bandaid bill that would extend unemployment benefits and highway funds and thwart drastic cuts to Medicare reimbursements. This morning, Bunning again blocked the Senate from taking up the measure for a vote, despite the fact that a fellow Republican, Senator Susan Collins of Maine, requested passage of a 30-day bill extension.

According to the LA Times, 41 transportation projects have been suspended, thousands of highway workers have been furloughed, and the benefits for about 100,000 unemployed Americans expired as of yesterday, because an extension was not passed. The 21% drop in Medicare reimbursement has been postponed, because the Centers for Medicare and Medicare Services (CMS) are delaying the processing of March claims.*

With respect to the Medicare cuts, James Rohack, MD, President of the American Medical Association said, "The Senate had over a year to repeal the flawed [SGR] formula that causes the annual payment cut and instead they abandoned America's seniors, making them collateral damage to their procedural games. Physicians are outraged because the cut, combined with the continued instability in the system, will force them to make difficult practice changes including limiting the number of Medicare patients they can treat."

Selected comments from practicing physicians at the AMA web site indicate that the drop in Medicare reimbursement will cause many physicians to dramatically reduce or eliminate Medicare patients from their practices. Practices that cater chiefly to elderly patients are likely to fold altogether.

According to USA Today, Senate Democrats are "planning an end-run around the unemployment and health benefits bill" by creating legislation that will extend benefits to the end of 2010. The stopgap measure, which would be retroactive, is due to come up for a vote next week.

* According to the American Academy of Neurology, the Centers for Medicare and Medicaid Services (CMS) extended its grace period for processing March claims from the 10th to the 17th. The CMS extension is made in anticipation of any retroactive legislation that will stave off Medicare cuts.

Update: In late developments, Bunning has relented and will allow a Senate vote tonight on the extension bill, reports USA Today.

03/03/10 update: Last night, President Obama signed a bill that enables an extension of the current Medicare reimbursement rates to April 1st, reports Medscape. A small poll at the website indicates that 65% of 40 physician respondents would stop or cut back on seeing Medicare patients, if the 21% cut in Medicare reimbursement had gone into effect. Medscape also reports that Senate Democrats are working on a longer-term fix, the American Workers, State, and Business Relief Act, which would delay the SGR formula-defined cuts in Medicare reimbursement to October 1st. Permanent fixes, specifically a House measure that repeals the SGR formula, are also in the works—although any such bill would add considerably to the federal deficit.  

Stenting of the carotid artery is a less invasive and potentially safer alternative to traditional endarterectomy (CEA) for the treatment of stenotic plaque. However, the relative efficacy of carotid stenting to prevent stroke has been unclear—a fact that has informed limited Medicare coverage for the procedure in the United States. Unfortunately the efficacy of carotid stenting remains unsettled after the recent release of conflicting results from 2 large, non-blinded studies.

Thursday the Lancet and Lancet Neurology published data from the International Carotid Stenting Study (ICSS), which showed a significantly higher incidence of ischemic stroke and related events after stenting. But results from the Carotid Revascularization Endarterectomy Versus Stenting Trial (CREST), which were presented Friday at the International Stroke Conference, revealed comparable rates of stroke, MI, or death with the 2 procedures.

Salient differences between the 2 studies, which include different patient populations and primary endpoints, are tabulated here. The main difficulty when attempting to conclude anything practical from the studies' results is that there are no easy apples-to-apples comparisons.

Trial Feature	ICSS (MRI Substudy)	ICSS		CREST
Location	Europe, Canada, Australia, New Zealand			United States, Canada
No. centers	7	50		100
Sponsorship	UK Medical Research Council, Stroke Association, Sanofi-Synthélabo, European Union, Netherlands Heart Foundation, Mach-Gaensslen Foundation	Medical Research Council, Stroke Association, Sanofi-Synthélabo, European Union		NINDS, Abbott Vascular (maker of Acculink carotid stent)
Patient no.	231	1713		2502
Carotid stenosis	Recently symptomatic			Symptomatic or asymptomatic
Primary outcome	30-day rate of new ischemic lesion on MRI		120-day rate of stroke or death or periprocedural MI*	30-day 4-year rate of death, MI, or stroke plus ipsilateral stroke thereafter
Stenting, %	33**		8.5**	7.2
CEA, %	8**		5.2**	6.8

* For interim safety analysis. The primary outcome of the ICSS is fatal or disabling stroke at 3 years; results are expected in 2012.
** Statistically significant, stenting vs CEA.

Those physicians who favor the CREST results in news reports propose that the positive outcomes with stenting are dependent on a high surgical skill level. Those physicians who favor the ICSS results note that, in CREST, the risks of periprocedural stroke and the composite outcome of death, MI, or stroke at 30 days were significantly higher with stenting (4.3% vs 2.3% and 5.2% vs 4.5%, respectively). They also cite previous studies (ie, the EVA-3S and SPACE trials) that failed to show the short-term equivalence of stenting. 

Upcoming post-hoc analyses of CREST may aid the identification of subpopulations (eg, those younger than 70 years of age) who are likely to realize more positive outcomes with carotid stenting. These data may inform the preferential use of carotid stenting in practice—at least when the surgeon is skilled in the procedure.

N.B.--One notable and underreported finding from the ICSS MRI substudy is that, in patients who received stents, embolic protection devices (like the FiberNet EP System) were associated with significantly higher rates of stroke (73% vs 34%). In patients who underwent CEA, the stroke rates with and without embolic protection devices were 17% and 16%, respectively. 

EVA-3S = Endarterectomy Versus Angioplasty in Patients With Symptomatic Severe Carotid Stenosis; NINDS = National Institute of Neurological Disorders and Stroke; SPACE = Stent-Supported Percutaneous Angioplasty of the Carotid Artery Versus Endarterectomy.

Anatomic diagram of the common, internal, and external carotid arteries from Gray's Anatomy (1918).

05/27/10 addendum: Peer-reviewed results of CREST are now available in today's issue of the NEJM and tabulated here. Although there was no clinical advantage with endarterectomy for the estimated 4-year combined primary outcome, endarterectomy edged out stenting for several secondary outcomes.

Outcome	Stenting	Endarterectomy	Statistical Significance
Estimated 4-year outcomes
Primary endpoint	7.2	6.8	P = .51
Stroke or death	6.4	4.7	P =.03
Symptomatic pts	8.0	6.4	P =.14
Asymptomatic pts	4.5	2.7	P =.07
Periprocedural outcomes
Death	0.7	0.3	P = .18
Stroke	4.1	2.3	P =.01
MI	1.1	2.3	P =.03
Post-periprocedural ipsilateral stroke	2.0	2.4	P =.85