Taking Trust With a Grain of Sodium

I was rather intrigued when a drug company representative showed up at my institution with some literature on a medication called Vaprisol manufactured by Astellas Pharma. This drug is one of a class of drugs called vasopressin receptor antagonists (VRA's) and is used to treat low blood sodium levels (also called hyponatremia).

I may be the worst philistine in academia but to me, Vaprisol is a so-so solution in search of a problem. Hyponatremia is typically treated by first identifying its underlying cause. Once that cause is determined, treating it generally makes the hyponatremia go away or at least improve. And guess what? Even if the problem can't be cured, the chronically low sodium that results rarely causes serious problems by itself.

That said, I can imagine rare scenarios whereby drugs such as Vaprisol may be useful. Obviously, attempting to be helpful, the rep left a reprint of a paper from the reputable American Journal of Medicine. It summarized some expert panel recommendations regarding the diagnosis and treatment of this condition.

I was surprised however to find that of the articles eight pages of text regarding the actual treatment of hyponatremia, half were devoted to VRA's. This may have been appropriate for a review of developments in the field but this was ostensibly a guideline for current management practice.

I encounter hyponatremia frequently but I've never seen nor known of a physician using this drug or any drugs in its class. I hardly think that the use of VRA's is generally accepted by the medical community. Which brings me to the title of my reportage. Are the recommendations of this guideline really trustworthy? Curious, I immediately flipped through the reprint to find the authors' financial relationships disclosure which had been dutifully reported.

I wasn't the least bit surprised that of the five authors, all five had financial ties to one or more of the companies selling VRA's:

Joseph G. Verbalis, MD, has served as a consultant and member of advisory boards and Speakers’ Bureau for Astellas Pharma US, Inc.; as a consultant and member of advisory boards for sanofi-aventis, and as a consultant to Otsuka.

Stephen R. Goldsmith, MD, has served as a consultant and member of advisory boards for Astellas Pharma US, Inc.

Arthur Greenberg, MD, has served as a member of advisory boards and Speakers’ Bureau for Astellas Pharma US, Inc., and as a consultant to sanofi-aventis.

Robert W. Schrier, MD, has served as a consultant to Otsuka.

Richard H. Sterns, MD, has served as a member of advisory boards and Speakers’ Bureau for Astellas Pharma US, Inc.

Now don't get me wrong. I myself haven't done an exhaustive search of the literature to determine whether or not these drugs are in fact any good. For all I know, they're magic bullets that should be put in the water supply to treat and prevent all current and future cases of hyponatremia.

But that's not my point. The problem is that even before checking out this particular drug's usefulness, I'm already starting from a position of mistrust. With such an undeniable "appearance of impropriety" how can I truly rely on these experts to give me the unvarnished truth? It's one thing to report hard facts. It's something entirely different to render an opinion which is what a guideline is.

Surveys of physicians have shown that most believe that the clinical judgment of other physicians can be influenced by financial encumbrances. However, those same doctors also believe that they themselves wouldn't be. What does this tell us?

Should any of us in medicine have unerring faith in the fairness and objectivity of our profession's opinion leaders and can we as patients trust that our doctors have access to the best information available? Perhaps we all need to read Dr. Daniel Carlat's 2007 New York Times article on his transformation from honest clinician to drug company shill (and back again).

It seems to me that we're getting to the point where we have to get away from the very concept of having clinical guidelines (not to mention FDA Advisory Committee reports) formulated by opinion leaders altogether. It may be far better to simply convene skilled but generic clinicians, epidemiologists, and statisticians with no ties to the pharmaceutical industry to create recommendations based only on a nonbiased, critical reading of the existing medical literature.

As drug reps are being increasingly isolated from prescribing physicians due to practice group and academic institution policies, pharmaceutical companies are shifting more of their advertising budgets towards cultivating (financial) relationships with academia's clinical gurus. No one can deny the moral hazard associated with this trend.

Understand that I am not impugning the integrity of the authors of the above-mentioned guideline but truthfully, I have no a priori reason to trust them either.

CPR Meets Evidence-Based Medicine Revisited

Big changes are brewing. Two articles were published in the most recent issue of Circulation. Both tend to support the notion that Continuous Chest Compression Cardiopulmonary Rescusitation (CCC CPR) using chest compressions only may be as effective as using both chest compressions and breathing.

Read more about why this is important here.Big changes are brewing. Two articles were just published in Circulation (here and here). Both tend to support the notion that Continuous Chest Compression Cardiopulmonary Rescusitation (CCC CPR) using chest compressions only may be as effective as with both chest compressions and breathing.

I wrote about Dr. Gordon Ewy's long struggle to convince the medical community of this possibility several years ago. I'm impressed that it looks like he may be vindicated.

CPR done immediately, prior to the arrival of paramedics, and by trained lay people has the potential for saving many lives and even for preventing the terrible consequences of cardiac arrest those who survive. The standard protocol (for adults) is to give the patient two breaths and then thirty chest compressions then alternating back and forth. The question is whether this is the best way. There is now increasing evidence that it is not.

Ewy, who wrote a previous review article on the subject was struck some years ago by a fascinating observation. A woman was attempting to resuscitate her husband using CPR as coached by an emergency

"Why is it that every time I press on his chest he opens his eyes, and every time I stop to breathe for him he goes back to sleep?"

This phenomenon has also been noted by previously by paramedics and among other things, caused Ewy to speculate that perhaps the breathing part of CPR isn't that important. Moreover, he questioned whether it was in fact harmful given that it prevented chest compressions from being done continuously.

Animal studies had suggested that the oxygenation during the breathing phase was not nearly as important as maintaining perfusion which only happens during chest compressions. In fact, it takes some "momentum" to maintain that perfusion which is lost when they are not done continuously.

The two studies linked above were observational studies but the first demonstrated that outcomes were similar in one month regardless of which type of CPR was done in the field (over 11,000 patients). The second showed that neurological outcome a year post-event was similar for the CCC CPR vs. conventional CPR.

For prolonged cases (resuscitations greater than 15 minutes), the second study showed a slight advantage for conventional CPR. This may represent what statisticians refer to as an alpha-error though (also known as a fake finding due to bad luck). The reason I say that is that even no CPR did better in those patients which to me doesn't make biological sense.

The big question and one that Ewy himself raises in the accompanying editorial, is whether there is now enough data to warrant a change in the general CPR guidelines given to perhaps millions of lay people worldwide eliminating the breathing portion. Certainly both of these new studies have enough holes in them to drive a semi through; but whether writing new guidelines on this issue has enormous implications for a simple reason.

One of the biggest barriers to people performing CPR on strangers is the "mouth-to-mouth" part. One survey Ewy did in the past showed that only 15% of lay people would be willing to do this. Eliminating this requirement could cause many people who would otherwise walk away to actually be willing to do CCC CPR. The public health consequences of such a change could be extraordinary.

The question is now becoming not so much whether there's enough evidence to recommend the change but rather whether there's enough evidence to continue teaching what may be a futile, deleterious practice.

Again, see my previous post for more information about this.