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.

**

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

What's in your health care shopping cart?

A few years ago, we received a letter from a physician reader who complained that the approximate prices of drugs provided in AFP were often quite different from the prices he found online or in his local drugstore. This letter ultimately led to a re-evaluation of the rationale and process for estimating drug costs in the journal, as AFP editor Jay Siwek, MD explained in this January 2010 editorial:

Given the difficulties of arriving at the cost of a course of therapy or a one-month prescription, and the wide range of prices possible, we wondered whether it was worth the trouble. So, we did what we regularly do when faced with questions like this—we surveyed our readers. The answer was loud and clear: you want representative prices listed, for generic and brand name drugs. You also prefer an actual dollar amount, or range, rather than using symbols such as $–$$$, as some drug formularies do. And, you found this information helpful when deciding among drugs or when counseling patients.

Although having information about the costs of drugs can be helpful, physicians are often unaware of the costs of common tests, procedures, and referrals. A recent commentary in JAMA argues that electronic medical records should incorporate such cost information to make clinicians aware of the overall costs generated by office visits and other health care encounters:

What if every time a practitioner used an electronic medical record system to order a procedure or test for a patient, an electronic shopping cart appeared, indicating how much that “purchase” would cost? What if at the end of the day the practitioner received a statement indicating precisely how much money he or she had ordered to be spent on behalf of patients? What would happen? Would anybody care? Some evidence suggests that providing this type of information to physicians may be helpful. For instance, in a study at one hospital, following the initiation of a weekly announcement informing the surgical house staff and attending physicians of the actual dollar amount charged to non–intensive care patients for laboratory services (ie, daily phlebotomy) ordered during the previous week, there were reductions in daily per-patient charges for laboratory services, with estimated cost savings of more than $50 000 over the course of the 11-week intervention.

The American Academy of Family Physicians has partnered with the American Board of Internal Medicine and several other physician and consumer groups in the Choosing Wisely campaign, an initiative to promote more efficient use of limited health care resources. Although this campaign focuses on reducing use of tests or procedures that have no clinical benefits (e.g., imaging for uncomplicated low back pain, antibiotics for upper respiratory infections), it raises the question of whether physicians should take responsibility for controlling costs of health care beyond simply eliminating "waste." For example, should family physicians' virtual "shopping carts" drive more selective use of health services that have high costs and marginal benefits (e.g., coronary CT scans, cancer screening in patients over age 75 years)? Or is this type of thinking unjustified and unethical rationing? What's your view?

The state of family medicine is ... ?

A special report on "The State of Family Medicine" in the current issue of AFP's sister publication, Family Practice Management, reviews data from 2011 Residency Match and American Academy of Family Physicians' member surveys to arrive at a mixed conclusion about the current status of the specialty:

On the one hand, family medicine has its challenges, including administrative hassles, a lack of support in the health care system, and threats to its comprehensiveness and scope of practice. On the other hand, family medicine has a lot going for it, including recent efforts to create primary care incentives, incomes well above the national average, and solid evidence of its value to the health care system.

Although the glass may appear to be either half-full or half-empty for today's family physicians, depending on one's perspective, there is a widespread consensus that there aren't nearly enough of us to handle the projected millions of new patients who will be seeking primary care as the result of health reform. An article published in last week's Washington Post quoted AAFP President Glen Stream, MD and Robert Graham Center for Policy Studies in Family Medicine and Primary Care director Robert Phillips, MD, MSPH on the urgent need to address the economic realities that drive many students away from careers in family medicine and primary care.

Since 2000, AFP has published a series of One-Pagers produced by the Graham Center that examine broad historical trends in the scope and practice of family medicine, the impact of policy changes on the primary care workforce, and the often underestimated benefits that primary care physicians bring to the U.S. health system. Collectively, they are an invaluable resource for illustrating the current "state of family medicine." The full text of each of these One-Pagers is available online without access restrictions from the date of publication.

How many referrals is too many?

Most AFP review articles about conditions that may require co-management of specialists contain a short section or Table titled "Indications for Referral." For example, the January 1st article on prevention and care of outpatient burns includes a list of criteria from the American Burn Association for considering the transfer of a patient to a burn center. This and other lists generally represent expert consensus on appropriate reasons to refer a patient in a typical primary care setting; obviously, availability and accessibility of specialists has a large influence on a family physician's practice with regard to management of "referable" conditions. Clinicians' training and expertise also affect their comfort levels in caring for patients with complex problems and, as previous studies have shown, these factors lead to variations in referral rates.

Despite variations in referral rates among individual physicians, there is a clear trend in the U.S. toward more referrals. An analysis of ambulatory care survey data from 1999 to 2009 recently published in the Archives of Internal Medicine found that the probability that an office visit resulted in a referral nearly doubled during this time period, from 4.8% to 9.3%. It isn't clear why this is happening, or what percentage of those referrals are appropriate. Medicine may be becoming more complex, or patients may be presenting with more problems that cannot be effectively dealt with in an office visit that is the same length as it was 10 years ago. What is clear is that at a time when a coalition of national primary and specialty care organizations is leading a campaign to reduce overuse of health care resources, the impact of this dramatic increase in referrals cannot be ignored. But in the absence of evidence-based standards for when to refer, how many referrals is too many? Is this even an answerable question? And if it is, what can be done about it?