Patents versus patients? Revisiting the Journal Club on donepezil 23 mg

In the March 15, 2011 issue of AFP, Drs. Mark Graber, Robert Dachs, and Andrea Darby-Stewart analyzed an industry-funded trial that compared the effects of two daily doses of the Alzheimer's disease drug donepezil (Aricept): a new 23 mg version and the existing 10 mg version that would soon lose its patent protection. Despite the trial authors' finding that the higher dose of donepezil slightly improved cognitive outcomes, AFP Journal Club commentators determined that this difference was clinically unimportant, and was greatly outweighed by the higher frequency of adverse effects in patients using the higher dose:

First, the authors did four comparisons. Three were negative and only one was positive. And the one that was positive was only two points different on a 100-point scale. So, although this is statistically significant, it is clinically meaningless. There is no discernible benefit for the patient or caregivers. ... Also, the drop-out rate in this study was an astounding 30 percent in the higher-dose group and 18 percent in the lower-dose group.

Adverse effects of donepezil include bradycardia, falls, nausea, diarrhea, and anorexia. In fact, a recent study demonstrated that community-dwelling older persons with dementia who are taking currently available cholinesterase inhibitors have higher rates of hospitalization for syncope, bradycardia, pacemaker insertion, and hip fractures compared with similar patients with Alzheimer disease who are not taking these medications. So, the idea of increasing the dose to 23 mg, potentially resulting in more serious adverse events while achieving no clinical gain, is ill-conceived at best.

Nonetheless, based on this study, the U.S. Food and Drug Administration eventually approved the 23 mg dose of donepezil against the advice of its own medical reviewers. One year later, though, the Journal Club on donepezil has proved to be prescient. Last week, in a scathing editorial published in BMJ, noted physician-researchers Lisa Schwartz and Steven Woloshin echoed AFP's earlier critique. They also rebuked the FDA for allowing Eisai, the manufacturer of donepezil, to include a false statement on the drug label and physician advertisements that touted "important clinical benefits" on measures of cognition (which, as noted, were clinically meaningless) and global function (which were not even statistically significant). Schwartz and Woloshin concluded by calling on the FDA to exercise greater oversight of such ethically questionable practices:

Alzheimer's is an awful disease. Sadly, the available drugs don't work well. But that is no excuse for emotionally manipulating vulnerable patients, desperate family members, and their doctors to use a product that is more likely to add harm than benefit. Nowhere - not in the direct to consumer or the physician advertisements, nor even in the FDA approved label - are the great uncertainties about this drug explained. ... That it is so easy to send doctors and patients incomplete and distorted messages about drugs is depressing. To make good decisions about drugs, doctors and patients need the evidence. The FDA should not forget to give it to them.

Smoking cessation: what works, and what doesn't

In the cover article of the March 15th issue of AFP, Drs. Michele Larzelere and Dave Williams review evidence-based strategies to promote smoking cessation, including the five A's framework (Ask, Advise, Assess, Assist, and Arrange), stages of behavior change, and motivational interventions. In addition, they provide practical information about first-line medical therapies that improve smoking cessation rates in adults: nicotine replacement, sustained-release bupropion, and varenicline.

Despite the existence of well-established guidelines for clinicians on applying these effective interventions in practice, however, one in five adults in the U.S. continues to smoke. This fact has led researchers to explore other ways to motivate smokers to quit, such as using imaging technology to show them the personal consequences of tobacco use. In a randomized trial recently published in the Archives of Internal Medicine, researchers tested the "pictures are worth a thousand words" theory by comparing cessation rates between smokers who received standard therapy plus carotid plaque ultrasonographic screening to smokers receiving standard therapy alone. Even though 58 percent of smokers in the intervention group were found to have carotid plaques, there was no statistical difference in cessation rates between the groups after one year, and patients with plaques were not more likely to quit smoking than those with normal ultrasound results.

In an accompanying editorial, Dr. Patrick O'Malley called for a renewed emphasis on developing communication skills throughout medical training:

We rely too much on technology and testing that are misapplied to problems that really should be addressed with cognitive, emotion handling, and relationship-centered skills. We need a paradigm shift in priorities and incentives to shift from excessive reliance on technologies, a terribly wasteful practice, to training and cultivation of communication- and relationship-based skills that are likely much more effective in the psychosocial domains of care.

The bottom line for family physicians: when it comes to promoting smoking cessation, talking to patients trumps technology.

Addressing gaps in end-of-life planning

A recent article by family physician Ken Murray in the Wall Street Journal, titled "Why Doctors Die Differently," observed that doctors are more likely than other people to decline end-of-life interventions that have little likelihood of benefit:

It's not something that we like to talk about, but doctors die, too. What's unusual about them is not how much treatment they get compared with most Americans, but how little. They know exactly what is going to happen, they know the choices, and they generally have access to any sort of medical care that they could want. But they tend to go serenely and gently.


Doctors don't want to die any more than anyone else does. But they usually have talked about the limits of modern medicine with their families. They want to make sure that, when the time comes, no heroic measures are taken. During their last moments, they know, for instance, that they don't want someone breaking their ribs by performing cardiopulmonary resuscitation (which is what happens when CPR is done right).

In a published survey of older physicians cited in the article, 64 percent of physicians had created an advanced directive, which Dr. Murray argues is essential to planning for end-of-life care: "Written directives can give patients far more control over how their lives end. But while most of us accept that taxes are inescapable, death is a much harder pill to swallow, which keeps the vast majority of Americans from making proper arrangements."

In the March 1st issue of AFP, Drs. G. David Spoelhof and Barbara Elliott review strategies for implementing advance directives in office practice. The authors recommend that family physicians have interactive discussions with patients regarding their end-of-life care preferences over multiple office visits, and they provide guidance for overcoming common patient- and physician-related barriers to completion of advance directives. A suggested approach for physicians is to bring up the topic of advance directives at routine visits for patients age 50 years or older and intensify discussions upon the diagnosis of a chronic and progressive illness such as cancer, heart failure, or dementia:

Following a realistic discussion of the patient's prognosis, the physician initiates a more in-depth discussion, including the proxy and family members as desired, that centers on the patient's care goals. Adding a values history to the advance directive may be helpful. After the discussion, the advance directive is updated and made as specific as possible. These issues should be readdressed periodically and as circumstances change. The last phase occurs with the onset of frailty or the need for long-term care. The discussion, centered on the patient's care goals, may result in consistent and specific physician orders regarding life-sustaining interventions.

To ensure that patients' end-of-life wishes are respected, advance directives should avoid vague language (e.g., "no heroics"), be shared with proxy decision-makers, and be made accessible in the medical record so that they are easily transferable to multiple levels of care.

Doctors should trust their clinical judgments

A physician reader of AFP submitted the following post.

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Many doctors have lost, or never acquired, the ability to make decisions based on clinical judgment after a detailed history, physical examination and basic laboratory tests. Instead, they substitute expensive diagnostic tools for clinical competence.

A case in point: a friend recently asked my opinion after her primary care physician noted a moderately elevated eosinophil level on a complete blood count. I remembered the common causes of this abnormality (allergies and parasitic infections) and asked some questions about recent changes in diet, use of herbal products, and travel. I also recalled seeing eosinophilia in patients with Hodgkin's disease and systemic vasculitides, but she was completely asymptomatic and had been told that her physical exam was normal. In reviewing the topic online, I read about other rare causes of eosinophilia, but told her that in my judgment the chance that she had ovarian cancer or any of these other conditions was extremely low. This was, after all, a healthy 35 year-old woman who regularly ran marathons.

Our job as physicians should be to educate patients so that they can make informed decisions. Based on the information I gave, my friend seemed comfortable with a "wait and see" approach. She was not particularly concerned, as she recalled an aunt having been told for years that she had an elevated eosinophil count. However, her doctor pushed her to see a hematologist. After she endured CT scans of her chest, abdomen and pelvis, followed by a bone marrow biopsy, she wrote again to ask my opinion. It seems that the hematologist had found nothing and now wanted her to see an infectious disease specialist.

What drives doctors to order tests that, in their hearts, they must know have a remote chance of being helpful? For some, it may be medical-legal considerations. For others, there is a financial incentive. But at a deeper level, I think it is that too many doctors are unable to live with medical uncertainty. They want a definitive answer, even when it is unlikely that it would alter the patient's long-term well-being. We must learn to trust our clinical judgments, and to educate our patients and involve them in decision-making, if we ever hope to rein in health care costs.

Robert G. Brown, MD
Lovettsville, VA
E-mail: olddocbob@hotmail.com