Thursday, October 26, 2006

Thoracic imaging for lung cancer screening-here we go again

In the October 26,2006 issue of the New England Journal of Medicine we find a clinical study and an editorial about lung cancer screening using CT which should rekindle the decades old arguments about this topic. ( Survival of Patients with stage I Lung Cancer detected on CT Screening, NEJM 355;17, p. 1763). So high profile are NEJM articles with pickup and amplification by the news media that I will not be surprised when smokers and possibly folks who worked around asbestos and possibly other lung carcinogens will be asking their physicians for chest CTs. A brief review of the current study is found here.

A convincing advocate of the value of imaging screening for early lung cancer has been Dr. Gary M. Strauss. Some of his views can be found here. When we talk about screening we have to talk about the difference between survival rate and mortality rate.The latter is defined as the total number of deaths from the disease in question divided by total number tested. Survival rate is defined as numbers of survivors after some time period divided by total number diagnosed with cancer. If the screening technique were to detect significant numbers of indolent cancers then the survival rate might appear to be improved after the institution of the screening test while the mortality rate might be unchanged. Prostate cancer screening with periodic PSA measurements is sometimes accused of being an example of that. After spending a few decades in the pulmonary disease business I was not impressed with the large number of indolent or clinically insignificant lung cancers.Every pulmonary doctor remembers the occasional case of cured lung cancer that happened to fortunately be detected by a chest xray done for whatever reason. The coin lesions (less than 3 cm by definition) have a much higher cure rate than lung cancers as a whole. All of that leads to the intuitive appeal l (or maybe just hope) that if we could come up with a way to catch lung cancer early the current rather dismal survival rate of lung cancer would improve.

Conventional wisdom contains the nugget that in regard to screening one should use the cause specific mortality as a measure of efficacy not the survival over a given time period.. Strauss has taken the opposite view. More of his thoughts can be found here and here and here.

This brings us to the current study,I-ELCAP aka The International EarlyLung cancer Action Program. It is survival rates that are emphasized in this study (so the issue of lead time bias has to be raised) and the numbers seem impressive. The study is very large with over 31,000 asymptomatic persons at risk of lung cancer being screening with low dose spiral CT and then evaluated with a detailed protocol that utilized followup CTs, PET scans and skinny needle biopsy. They report a "estimated 10-year survival of 88% in the subgroup with clinical stage I lung cancer"

A great deal has happened since the early chest x-ray lung cancer screening projects. We have spiral CT, PET scans and skinny needle biopsies.Perhaps we can now detect lungs cancer early enough (that is small enough?) to remove them while they is still time. Before I reviewed the article I had assumed they were talking about non-small cell cancers (NSCLC) since the small cell variety seems to be another animal entirely. However, no mention is made on survival for each cell type or any indication that they were managed differently and there were 7 small cell cancers detected on the annual screening.Were they resected also? Is it possible that we can actually detect and remove small cell lung cancers that are so early they have not spread? In fact, there are some data indicating long term survival for small cell lung cancers treated with resection.

Friday, October 20, 2006

"Marketing strategies masquerading as Evidence Based Medicine"

A commentary appears in the October 19,2006 issue of the New England Journal of Medicine regarding allegations about the length to which a drug company will go in influencing patient care by misleading physicians and improperly manipulating the creation of treatment guidelines. The commentary in the Perspective section is entitled " Surviving Sepsis-Practice Guidelines, Marketing Campaigns, and Eli Lilly".The authors are all from the Critical Care Medicine Department at NIH. A summary of their article can be found on the October 19 post on Health Care Renewal.

Xigris (drotrecogin, aka recombinant human activated protein C,rhPAC) is the drug, Lilly is the drug company and the condition for which treatment guidelines were said to be manipulated is sepsis. I have been concerned for some time about the degree to which Big Pharma have used ( and mis- used) the concepts of evidence based medicine to promote various medications but if the commentary accurately reflects reality this example rivals or even exceeds the gabapentin story.

This NEJM article and an earlier article in the Annals of Internal Medicine dealing with gabapentin and the disreputable techniques used to market it ( I posted about it here ) should be mandatory reading for medical students and included in the reading lists of med school courses on EBM and how EBM can be kidnapped and exploited . If the situation is, in fact, as described in the NEJM commentary, egregious is not strong enough an adjective for that type behavior. But "If" is the operative word. For a thoughtful counterpoint to the NEJM commentary to to the Oct 22, 2006 post by Dr. RW. He reminds us that criticism of guidelines or for that matter any treatment should not be based simply on the fact that a drug company may have used various techniues to promote it but should be based on logic and reference to solid evidence and in his analysis of the NEJM article the authors from the NIH fall short in that category.

No one is shocked by the fact that businesses not infrequently promote their goods or services by emphasizing the advantages and minimizing the downside of their products. However, if and when that spin puts patients well being or lives at risk I believe we move past "mere" unethical behavior. There is little room for error in the treatment of sepsis patients and underplaying or ignoring the risk of hemorrhage from activated protein C (Xigris) could well lead to patient fatalities. (The authors assert that the risk of bleeding was not properly noted in the promotional material generated for Xigris). To withhold information about serious side effects from a medication and promote its use by deceptive means included sponsoring guidelines may well move past negligence as well.

There is more .Go to the October 20,2006 post from Health Care Renewal for expression of concern about the role another drug company, Amgen, played in the development of guidelines for uses of Epogen in renal failure.

I do not know if and/or to what degree the experts who authored the two guidelines mentioned above were actually improperly influenced by the drug companies' activities and/or recommended treatments for which the evidence was insufficient but the perception that guidelines might be "usurped ...for commercial purposes" has to make physicians even more skeptical of guidelines in general particularly with such a commentary in a high impact journal. Further, when you consider the uses to which guidelines are put,including quality audits,pay for performance,arguments in legal proceedings it becomes even more important that we know how the sausages are made. And as the NEJM article asserts Xigris does seem to have found its way into performance standards even though I believe it is fair to say that the jury is still out ( or should be) regarding its efficacy and safety.

Thursday, October 19, 2006

Basis for "Treat to goal" for cholesterol is questioned by Annals Internal Medicine review

A thought provoking-and in a way troubling review- in the October 3, 2006 issue of the Annals of Internal Medicine ( "Lack of Evidence for recommended Low-density Lipoprotein treatment Target: A solvable Problem" by R.A. et al Haywood) was highlighted on October 17,2006 by DB's Medical Rants and by MEDPUNDIT. It questions the evidentiary basis of NCEP's 2004 "treat to goal" set of recommendations. Haywood's article is instructive because of the thoughtful analysis of the data linking cholesterol level and response to statin therapy and outcome and troublesome because it raises doubt about the validity of adherence to the NCEP recommendations of treating to goal. I 'll have to admit that I accepted those targets as a reasonable thing to do leading to at times increasing the statin dose and sometimes adding ezetimibe. In 2004, the NCEP expert panel recommended that physicians treat patients at what they designate at "very high risk" for coronary events to achieve a LDL cholesterol of less than 70 and for those patients judged to be at " high risk" a value of less than 100.

The review's major point is this:

High quality data is lacking to provide basis for the recommendation to titrate lipid lowering therapy to LDL targets or to prove that such therapy is superior to simply prescribing doses of statin drugs used in the clinical trials for patients at high and very high cardiovascular risk.

It should be noted that the authors are quick to point out that they are not saying that there is strong evidence against the current recommendations.

The reply from Dr.Scott Grundy and the NCEP folks likely will be interesting. (I assume they have to reply to this). As thoughtful as this article is you have to wonder how much of an impact it will have.The cardiologists and a number of primary care doctors seemed to have accepted the lower goals rather widely and that concept may be a hard one to get back into the barn. At this point I do not know if we should try to or not.

Wednesday, October 11, 2006

More bad news regarding second generation antipsychotics.

The October 12, 2006 issue of The New England Journal of Medicine published an article regarding the use of the second generation antipsychotic drugs (SGAs) in the management of aggression and agitation and psychotic behavior in dementia. These drugs are widely used for this application although it is not approved (by the FDA) for that use and in fact there is a "black box" warning regarding increased risk of death in older patients with dementia.

Three drugs were compared with placebo in 421 patients in a multi center study; 1) olanzapine (Zyprexa), 2) risperidone (Risperdal) and 3)quetipine (Seroquel).

This trial differed from the typical efficacy-safety RCT done by drug companies as it looked at a "real clinical life" end point of time of discontinuing the medication because of any reason. The other primary outcome was the number of patients who had a minimal improvement a clinical behavior scale.

The authors concluded that the three drugs were more effective than placebo but the incidence of side effects limited their use. As seems to be more and more the case in clinical trials, there are so many comparisons made and often with rather arcane statistical tools it is difficult to know what to conclude. For example, Zyprexa was significantly better than placebo with the "Cox model" but not when compared with placebo with the "Hockberg adjustment" for multiple comparisons.Apparently this adjustment is an alternative to the Bonferroni technique to decrease the number of "false positives" when multiple comparisons are made. But how do you decide which technique to use-in this case the resultant answers seems 180 degrees apart.

Although the headline news- sound bites about this article may claim these drugs were useless, that characterization seems too simple.They can help control the symptoms of interest but often have to be discontinued because of side effects . Even the authors seems a bit ambivalent in their comments about the results;

"...our findings suggest that there is no large clinical benefit of treatment with atypical antipsychotic medications as compared with placebo."

They also say:

"Although the atypical antipsychotic drugs were more effective than placebo, adverse effects limited their overall effectiveness."

My take on all of this is these drugs may help a bit in the control of agitation and aggression in dementia patients but in a significant number of patients side effects lead to their discontinuation. Certaintly the exuberant enthusiasm driven in no small measure by drug company hype is waning. These drugs are not nearly as good as the efforts to promote them suggested. It would have been interesting and perhaps instructive for Haldol to have been included in the drugs that were compared in this study as for years it has been the stand by drug in difficult situations with dementia patients with aggressive behavior.

Sunday, October 08, 2006

Answering services should not make it hard to talk to physician

A recent article in the September/October issue of the Journal of the American Board of Family Practice by David Hildebrandt called attention to an issue with some answering services techniques that serve to prevent patients from contacting their physicians. By simply being asked "Is this an emergency?", many contacts with the physician are eliminated. Patients often call their doctor because they do not know if the issue is serious enough to be considered an emergency or not. This "filtering" technique does not serve the interests of the patient.Procedural barriers limiting contact with doctors cannot be in the physicians' s best interests either.

The survey admittedly was small, only 35 physicians offices were contacted and of those 14 used answering services and 9 of those asked the patients to decide if their call should be fowarded to the doctor. The small sample size precludes robust conclusions about how widespread the practice might be. An larger earlier study by the same lead author involved 91 primary care offices and in 55 the answering services "forced" the patients to decide if it was an emergency requiring a call back from the physician. Clearly ,this is not a good practice but I have encountered worse. I have attempted to contact physicians after hours, and sometimes on Friday afternoon and been unable to contact them at all or anyone providing coverage. The answering machine-not even a human- informs the caller what the office hours are and that if they have an emergency they should go to the nearest emergency room.

Another approach is the nurse telephone triage. While this is better I have some uneasy feeling about this as well. When you get old and cranky you tend to think if things are not done like you did them they are off base. When I was in private practice all calls were referred by the answering service to either the patient's physician or the on call doctor.

Dr. Bruce Bagley,the medical director for quality at the American Academy of Family Physicians, is quoted in the American Medical News story about the article:

"You want the highest level clinical person determining what's an emergency, not a person at an answering service who knows nothing from nothing."

Friday, October 06, 2006

Is Merck gearing up for "son of Vioxx"?

The editorial commentary by David Graham in the October 4,2006 issue of the Journal of the American Medical Association ("COX-2 Inhibitors,other NSAIDs and cardiovascular Risk,The seduction of Common Sense" vol. 296,no 13 p 1653) is very critical in regard to both Merck and the FDA. If Dr. Graham's analysis is correct Merck is already cooking the books to get a Vioxx like drug approved by the FDA. Admittedly, this is Dr. Graham's analysis of the pre-approval activities of Merck and their version of those activities is likely to differ significantly from his comments and for those we will have to wait a while.

Here is what he said- Merck has announced they will proceed to get approval for etoricoxib,a new COX-2 inhibitor. They will rely , in part, on the results of the MEDAL trial in which etoricoxib was compared with diclofenac and found to demonstrate that the cardiovascular event risk was the same with either medication using a "noninferiority study" design, which according to Graham, is "especially poor" at identifying risk between drugs. Further, the comparator drug was diclofenac which apparently has been associated with an increased risk of c-v events. By inference, he argues etoricoxib must also increase c-v risk.

Graham then says;

"This veiled and misleading ambiguity has much in common with the stratagems used by VIGOR and APPROVe,where the true results were opposite to those claimed and promoted."

There are two articles regarding COX-2 inhibitors in the same issue, one of which demonstrates an increased risk of cardiovascular events with diclofenac.One is a meta-analysis of randomized clinical trials (RCTs) dealing with renal effects and cardiac rhythm problems and the other a systematic analysis of observational studies. It is the latter which provides the following:

The relative risks (RR) of cardiovascular events is elevated with lower and higher doses of celecoxib-1.33 for the 25 mg/day dose and 1.64 for the greater than 25 mg /day dose.

The highest RR reported is with diclofenac at 1.50 while no increased risk is noted with naproxen and ibuprofen but idomethacin's RR is increased at 1.36.(Ref.Cardiovascular Risk and Inhibition of Cyclooxygenase,McGettigen P and Henry,D JAMA vol 296,no 13,p 1633)

The authors make an important comment :

"Typically, in pharmacoepidemiological studies there is reluctance to accept as causal RR estimates much below 2" This is because this type of study is subject to various biases but, predictably, the authors still believe the demonstrated association "are real". (When do authors not believe what they find is true?)

Here is a related quote form David Sackett et al in their second edition of "Evidence Based Medicine" (Churchhill Livingstone reprinted 2001, p.163)

"How Big should relative risk and odds ratios be before we should be impressed by them? ....We might not want to label an odds ratio from a case-control study as impressive unless it is greater than cohort studies..we might regard a relative risk of greater than 3 as convincing for more serious adverse events"

This systematic analysis utilized data from both case control and cohort studies so somewhere between 3 and 4 might be the threshold for concern according to the Canadian gurus of Evidence based medicine and these were all under 2.

Even though one can argue about causality and relative risk level this issue of JAMA will do little to encourage the use of COX-2 drugs. Graham's suggestion of using naproxen (or ibuprofen) plus a proton pump inhibitor (PPI) as an alternative makes sense and is what I was recommending for the last several years.

Thursday, October 05, 2006

Second generation antipsychotics-efficacy versus effectiveness

In the 1960s, the phenothiazines changed the face of psychiatry when chlorpromazine was shown to be effective treatment for schizophrenia. These first generation antipsychotics (FGAs) are associated with major side effects-namely acute extrapyramidal symptoms and tardive dyskinesia. So when the first of the second generation antipsychotics(SGAs),clozapine,was approved by the FDA and it seemed to be less likely to cause these very troublesome side effects another new era in psychiatric therapeutics seemed to be launched. Other SGAs were developed and approved and were widely accepted and generally believed to not only be more efficacious regarding the so-called negative symptoms of schizophrenia but safer and capable of inducing a better quality of life.The evidence that clozapine did in fact produce superior results in symptom reduction in patients resistant to other drugs is convincing: the question seems to be are the other drugs (five have been approved in the last ten years) in the second generation category also superior.

In 2005 and 2006, two clinical trials (CATIE and CUtLASS1) were published which have raised considerable doubt about the alleged superiority of these SGAs. (Thanks to PHARMAGOSSIP for the reference.)

Dr. Jeffery Lieberman from Columbia Psychiatry Department published an excellent commentary on this issue and his article is available on line full text from the AMA site (go to "Newsroom" and then to "Publications" for the comments found in the October 2006 issue of the Archives of General Psychiatry.Also full text free links to the Studies are found in his reference list)

The issue of the relative value of the FGAs and the SGAs is important per se.Dr. Lieberman's comments not only address that but also the broader issue which can be stated as follows:

How can the following happen-A medication is approved by the FDA based on Phase 2 and Phase 3 RCTs, becomes widely accepted largely replacing the older drugs with that application and then following more Scrutiny and analysis is found to not be any better than the drug(s) it replaced?

He suggests two reasons"

1.The traditional efficacy-effectiveness gap. Things do not always work out the same in the helter-skelter world of clinical medicine as they do in the sometimes cherry picked world of randomized clinical trials. The second Gaultian axiom of evidence based medicine is that "Treatments do not work as well in the clinical practice as they do in randomized trials and they cause more problems".(The first axiom is "The basic fact of clinical trials is that everyone does not respond the same to a particular treatment and almost no one has the average effect")

2.Claims of a drug's superiority were "greatly exaggerated". Drug company hype and overt and sometimes covert promotional activities certainly play a role as does (and this is my contribution to that reason) the sincere desire of physicians to be able to have better tools and be better able to treat their patients. In other words, docs yearn for better drugs and sometimes overlook the weakness of the evidence that is presented.

There will be much more written about whether FGA or SGA are better or safer and neither Dr. Lieberman nor I claim to have the final word.But if there is a lesson here I think it is that because of the efficacy-effectiveness gap a RCT (or even several RCTs) is/are just the beginning of the process of deciding what to do for a given patient; it is not the determining factor and we often cannot really judge the value of a given treatment until there is enough real world clinical experience to see how it really works.

Tuesday, October 03, 2006

The virtual doctor's lounge-the successor to the now defunct real lounge

I written before about the demise of the doctor's lounge in the hospital-the previous site of free coffee, curb stone consultations, physician networking and the sharing of common shared interests and experiences and a chance to vent about whatever. My regular 4 or 5 readers will not be surprised that I blame this on managed care.

In a way, medical blogs have become a surrogate for this experience for physicians many of whom have significantly less face time with other physicians and according to one surgeon blogger even telephone time has become less common as more and more PAs and NPs are delegated the role of calling the consultant.

Today, for example, in this virtual lounge I learned useful information about neuropathic pain from Doctor RW and was reminded by DB about the importance of time in the context of taking it to explain prescription medication to your patients.Memories of 40 years ago were recharged by Dr. Schwab in his comments about the medical drama of a surgeon opening a chest in the emergency room. Medpundit gives me a chuckle when she relates what British soldiers in Iraq think of the British NHS when they claim they would rather get shot in the head and get to go to a great US military hospital or receive a less serious wound and end up in the NHS. As usual the pulmonary docs at their site present fascinating cases.

The medical web does provide some of what we had at the lounge (we can certainty vent 24-7) and in some ways much more in terms of connectivity with information but I think how great it would be if had both.Sitting down over coffee and discussing a difficult case with a respected colleague is something many of us miss.