Ethics: March 2010 Archives
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 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 |
Neutral |
MI Risk |
|
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 |
Neutral |
Disfavor Use |
|
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.
