A Focus on Fees: Why I Practice Evidence Based Medicine Like I Invest for Retirement

He is the best physician who knows the worthlessness of the most medicines."  - Ben Franklin

This blog has been highly critical of evidence, taking every opportunity to strike at any vulnerability of a trial or research program.  That is because this is serious business.  Lives and limbs hang in the balance, pharmaceutical companies stand to gain billions from "successful" trials, investigators' careers and funding are on the line if chance findings don't pan out in subsequent investigations, sometimes well-meaning convictions blind investigators and others to the truth; in short, the landscape is fertile for bias, manipulation, and even fraud.  To top it off, many of the questions about how to practice or deal with a particular problem have scant or no evidence to bear upon them, and practitioners are left to guesswork, convention, or pathophysiological reasoning - and I'm not sure which among these is most threatening.  So I am often asked, how do you deal with the uncertainty that arises from fallible evidence or paucity of evidence when you practice?

I have ruminated about this question and how to summarize the logic of my minimalist practice style for some time but yesterday the answer dawned on me:  I practice medicine like I invest in stocks, with a strategy that comports with the data, and with precepts of rational decision making.

Investors make numerous well-described and wealth destroying mistakes when they invest in stocks.  Experts such as John Bogle, Burton Malkiel, David Swenson and others have written influential books on the topic, utilizing data from studies in economics (financial and behavioral).  Key among the mistakes that investors make are trying to select high performers (such as mutual funds or hedge fund managers), chasing performance, and timing the market.  The data suggest that professional stock pickers fare little better than chance over the long run, that you cannot discern who will beat the average over the long run, and that the excess fees you are charged by high performers will negate any benefit they might otherwise have conferred to you.  The experts generally recommend that you stick with strategies that are proven beyond a reasonable doubt: a heavy concentration in stocks with their long track record of superior returns, diversification, and strict minimization of fees.  Fees are the only thing you can guarantee about your portfolio's returns.

PCI versus CABG - Superiority is in the heart of the angina sufferer

In the current issue of the NEJM, Serruys et al describe the results of a multicenter RCT comparing PCI with CABG for severe coronary artery disease: http://content.nejm.org/cgi/content/full/360/10/961. The trial, which was designed by the [profiteering] makers of drug-coated stents, was a non-inferiority trial intended to show the non-inferiority (NOT the equivalence) of PCI (new treatment) to CABG (standard treatment). Alas, the authors appear to misunderstand the design and reporting of non-inferiority trials, and mistakenly declare CABG as superior to PCI as a result of this study. This error will be the subject of a forthcoming letter to the editor of the NEJM.

The findings of the study can be summarized as follows: compared to PCI, CABG led to a 5.6% reduction in the combined endpoint of death from any cause, stroke, myocardial infarction, or repeat vascularization (P=0.002). The caveats regarding non-inferiority trials notwithstanding, there are other reasons to call into question the interpretation that CABG is superior to PCI, and I will enumerate some of these below.

1.) The study used a ONE-SIDED 95% confidence interval - shame, shame, shame. See: http://jama.ama-assn.org/cgi/content/abstract/295/10/1152 .
2.) Table 1 is conspicuous for the absence of cost data. The post-procedural hospital stay was 6 days longer for CABG than PCI, and the procedural time was twice as long - both highly statistically and clinically significant. I recognize that it would be somewhat specious to provide means for cost because it was a multinational study and there would likely be substantial dispersion of cost among countries, but it seems like neglecting the data altogether is a glaring omission of a very important variable if we are to rationally compare these two procedures.
3.) Numbers needed to treat are mentioned in the text for variables such as death and myocardial infarction that were not individually statistically significant. This is misleading. The significance of the composite endpoint does not allow one to infer that the individual components are significant (they were not) and I don't think it's conventional to report NNTs for non-significant outcomes.
4.) Table 2 lists significant deficencies and discrepancies between pharmocological medical management at discharge which are inadequately explained as mentioned by the editorialist.
5.) Table 2 also demonstrates a five-fold increase in amiodarone use and a three-fold increase in warfarin use at discharge among patients in the CABG group. I infer this to represent an increase in the rate of atrial fibrillation in the CABG patients, but because the rates are not reported, I am kept wondering.
6.) Neurocognitive functioning and the incidence of defecits (if measured), known complications of bypass, are not reported.
7.) It is mentioned in the discussion that after consent, more patients randomized to CABG compared to PCI withdrew consent, a tacit admission of the wariness of patients to submit to this more invasive procedure.

In all, what this trial does for me is to remind me to be wary of an overly-simplistic interpretation of complex data and a tendency toward dichotimous thinking - superior versus inferior, good versus bad, etc.

One interpretation of the data is that a 3.4 hour bypass surgery and 9 days in the hospital !MIGHT! save you from an extra 1.7 hour PCI and another 3 days in the hospital on top of your initial committment of 1.7 hours of PCI and 3 days in the hospital if you wind up requiring revascularization, the primary [only] driver of the composite endpoint. And in payment for this dubiously useful exchange, you must submit to a ~2% increase in the risk of stroke, have a cracked chest, risk surgical wound infection (rate of which is also not reported) pay an unknown (but probably large) increased financial cost, risk some probably large increased risk of atrial fibrillation and therefore be discharged on amiodarone and coumadin with their high rates of side effects and drug-drug interactions, while coincidentally risk being discharged on inadequate medical pharmacological management.

Looked at from this perspective, one sees that beauty is truly in the eye of the beholder.

Prophylactic Cranial Irradiation: a matter of blinding, ascertainment, side effects, and preferences

Slotman et al (August 16 issue of NEJM: http://content.nejm.org/cgi/content/short/357/7/664) report a multicenter RCT of prophylactic cranial irradiation for extensive small cell carcinoma of the lung and conclude that it not only reduces symptomatic brain metastases, but also prolongs progression-free and overall survival. This is a well designed and conducted non-industry-sponsored RCT, but several aspects of the trial warrant scrutiny and temper my enthusiasm for this therapy. Among them:

The trial is not blinded (masked is a more sensitive term) from a patient perspective and no effort was made to create a sham irradiation procedure. While unintentional unmasking due to side effects may have limited the effectiveness of a sham procedure, it may not have rendered it entirely ineffective. This issue is of importance because meeting the primary endpoint was contingent on patient symptoms, and a placebo effect may have impacted participants’ reporting of symptoms. Some investigators have gone to great lengths to tease out placebo effects using sham procedures, and the results have been surprising (e.g., knee arthroscopy; see: https://content.nejm.org/cgi/content/abstract/347/2/81?ck=nck).


We are not told if investigators, the patient’s other physicians, radiologists, and statisticians were masked to the treatment assignment. Lack of masking may have led to other differences in patient management, or to differences in the threshold for ordering CT/MRI scans. We are not told about the number of CT/MRI scans in each group. In a nutshell: possible ascertainment bias (see http://www.consort-statement.org/?o=1123).

There are several apparently strong trends in QOL assessments, but we are not told what direction they are in. Significant differences in these scores were unlikely to be found as the deck was stacked when the trial was designed: p<0.01 was required for significance of QOL assessments. While this is justified because of multiple comparisons, it seems unfair to make the significance level for side effects more conservative than that for the primary outcome of interest (think Vioxx here). The significance level required for secondary endpoints (progression-free and overall survival) was not lowered to account for multiple comparisons. Moreover, more than half of QOL assessments were missing by 9 months, so this study is underpowered to detect differences in QOL. It is therefore all the more important to know the direction of the trends that are reported.

The authors appear to “gloss over” the significant side effects associated with this therapy. It made some subjects ill.

If we are willing to accept that overall survival is improved by this therapy (I’m personally circumspect about this for the above reasons) the bottom line for patients will be whether they would prefer on average 5 additional weeks of life with nausea, vomiting weight loss, fatigue, anorexia, and leg weakness to 5 fewer weeks of life without these symptoms. I think I know what choice many will make, and our projection bias may lead us to make inaccurate predictions of their choices (see Lowenstein, Medical Decision Making, Jan/Feb 2005: http://mdm.sagepub.com/cgi/content/citation/25/1/96).

The authors state in the concluding paragraph:

“Prophylactic cranial irradiation should be part of standard care for all patients with small-cell lung cancer who have a response to initial chemotherapy, and it should be part of the standard treatment in future studies involving these patients.”

I think the decision to use this therapy is one that only patients are justified making. At least now we have reasonably good data to help them inform their choice.