Primecuts – This Week In The Journals

September 20, 2010

By Jennifer Dong, MD

Faculty Peer Reviewed

In health news this past week, there has been a significant focus on the obesity problem in the United States as well as closer attention to medical education and the quality of healthcare physicians deliver in the current system.

Both the New York Times and Reuters online reported this week that U.S. advisors have rejected the new Arena weight-loss drug, Lorcaserin, which works by mimicking serotonin in the brain and suppressing the appetite.[1,2] A committee of medical experts voted 9-5 that the risks were greater than the possible benefit of moderate weight loss. Some physicians support the use of Lorcaserin, citing an urgent need for new diet drugs since obesity affects one third of adults in our country and at least another one third are overweight.[1] However, the FDA is concerned about the safety profile of Lorcaserin because testing at high doses has shown tumor growth in rats. The committee is concerned about the potential development of cancer in humans, which has not yet been supported in studies. Arena and Eisai Co. of Japan believe the drug has “a positive benefit-risk profile” and according to chief executives, Arena “will work closely with the FDA” on its review. The FDA’s final ruling is pending in October. If the ruling is in favor of Lorcaserin, this drug could be very promising and potentially produce strong sales if it makes it to market. In the meantime, two other drugs from Vivus, Inc. and Orexigen Therapeutics, Inc. are currently in the pipeline for weight loss, although the Vivus diet drug was recently rejected in July.[1,2] It looks like we will need to continue counseling our patients that there is still no magic pill for weight loss yet, although a few investigational drugs seem promising.

Time magazine this week also featured an article about FDA-approved machines designed to fight fat.[3] There appears to be two machines on the horizon – the Zeltiq Coolsculpting system and the Zerona – that can either freeze or deflate fat cells to help with weight loss. The FDA recently approved these devices for use in doctor’s offices to provide “body contouring treatment”.  The idea is that the Zeltiq freezes fat cells to disintegrate them over time, while the Zerona basically “pops” adipocytes with subsequent degradation by the body. There are some concerns that the mechanisms of these devices are too simplistic, since appetite regulation is more complex when hormones and metabolism are taken into consideration. Others are also concerned that quick disintegration of fat cells might lead to problems with blood toxicity.[3] Now that these machines are FDA-approved, it will be very interesting to see if they become popular in the outpatient setting in our effort to help patients lose weight.

Dr. Pauline Chen writes a health column for the New York Times and this week raised the question about how to address the nutrition gap in medical education.[4] Even after having completed her residency, Dr. Chen says that she feels unprepared to discuss diet advice with her patients. Rather than shy away from the topic and reflexively refer patients to a dietitian, we should feel more comfortable discussing diet, especially since it plays such a crucial role in improving health outcomes in our patients. In the mid-1980s, the National Academy of Science published an important report highlighting the lack of adequate nutritional education in medical schools and recommending that a minimum of 25 hours of nutritional instruction be part of the medical curriculum. Nowadays almost all medical schools require exposure to nutrition; however, the University of North Carolina at Chapel Hill surveyed over 100 medical schools and found that only about 25% offered the recommended 25 hours of nutritional instruction. Over the past 15 years, UNC has created an online instructional course entitled Nutrition in Medicine to address topics like the molecular mechanism of cancer nutrition, obesity in children, dietary supplements, and nutrition in the elderly. This online program has been offered to Texas Tech School of Medicine and already seen great results. It is also flexible, allowing medical students on clinical rotations in geographically scattered hospitals to continue learning about diet and counseling patients. Individuals at UNC are also working on online nutritional programs directed toward practicing physicians with the goal of filling these knowledge gaps for older doctors.[4] Hopefully, with these educational measures, we will develop more confidence and knowledge to advise our patients on what they should or should not eat.

In other health-related news, included an editorial by an NYU Internal Medicine attending, Dr. Danielle Ofri, who comments on what makes a “good” doctor and whether there really are any good measures for “quality” in medicine.[5] She states that currently the use of physician report cards is flawed and controversial since such tools are created with pieces of patient-care data and are not representative of how complex patient care can really be. Sadly, our current healthcare system is impossibly complicated, so deriving “quality measures” to assess who makes a good doctor versus a bad one is incredibly difficult. The quality of care also depends largely on the setting in which resident and/or attending physicians practice. She referred to a JAMA study[6] suggesting that doctors who care for patients with significant challenges, such as low socioeconomic status, underinsurance, and language barriers, deliver poorer quality of care. Without being able to control for such factors, it seems to be that pre-set quality measures in the physician report cards do not accurately reflect who makes a good doctor, and requires further studying.

This week’s issue of JAMA centered on the theme of medical education. One particular article investigated and discussed the type of cognitive biases and reasoning internal medicine residents utilize when making diagnoses. This experimental study took place in the Netherlands and included 18 first-year internal medicine residents and 18 second-year internal medicine participants.[7] The study was conducted in three phases using pre-defined clinical cases with known diagnoses: in Phase 1 (exposure) participants were required to evaluate the accuracy of a diagnosis provided for 6 different cases; in Phase 2 (non-analytical diagnosis) participants were instructed to diagnose 8 new cases, 4 of which had clinical features similar to the diseases encountered in phase 1; and in Phase 3 (reflective diagnosis) participants were asked to reflect on the diagnosis of the 4 cases that could have been influenced by availability bias in Phase 2. Availability bias refers to the concept of availability heuristic, which is the tendency to weigh the likelihood of things by how easily they are recalled and which may lead physicians to erroneously make a diagnosis based on how frequently it comes to mind. The mean diagnostic accuracy scores were based on a perfect score of 4.0 and a separate assessment of how accurately the participants diagnosed the cases. An availability bias occurred in the non-analytical reasoning approach among the second-year residents, who scored lower on the cases similar to the ones previously seen in Phase 1 than on the other cases. The study did not observe this pattern as frequently among the first-year residents, who had a higher score on the cases similar to those encountered in phase 1 than on the other cases. In addition, there was a significant effect indicating that reflection improved all participants’ diagnoses when compared with non-analytical reasoning for first-year residents and for second-year residents. Essentially, this study demonstrates that availability bias indeed does creep in when medical residents use a non-analytical approach to diagnostic reasoning. It also suggests that reflective reasoning might help to counteract this bias. This availability bias appears to depend on the mode of reasoning utilized (non-analytical versus analytical) and the level of expertise of the physician. This study indicates that the process of reflection may be a mechanism to counteract such cognitive biases. In summary, this study tells us that as we move on through residency, we should understand that we may rely more and more on availability bias to make medical diagnoses and not just think about the last case we saw that was similar. It’s important to recognize that we may need to take a little extra time to reflect on complex cases to ensure accurate diagnosis and subsequent management.

In the medical journals, the New England Journal of Medicine provided additional findings from the Evaluation of COPD Longitudinally to Identify Predictive Surrogate Endpoints (ECLIPSE) study. This is a large observational cohort study that analyzed the frequency and associations of exacerbation in a large cohort of COPD patients.[8] A participant was considered to have an exacerbation based on the patient’s primary care physician’s clinical decision to treat the patient with antibiotics or corticosteroids (or both) or whether the patient required hospitalization. While the study examined other independent factors affecting exacerbation frequency, such as health care quality of life, reduced FEV1, history of reflux, and baseline white blood cell count, the authors found that the single best predictor of COPD exacerbation is a history of exacerbation in the previous year (odds ratio, 4.30; 95% CI, 3.58-5.17, p<0.001). According to the study, the exacerbation rates in the first year of follow-up were 0.85 per person for patients with stage 2 COPD (per GOLD stage definitions), 1.35 for patients with stage 3 COPD, and 2.0 for stage 4 COPD patients. Over the three-year study period, the exacerbation frequency remained relatively stable. Among patients who had frequent exacerbations in years 1 and 2, 71% went on to have frequent exacerbations in year 3, and among those with no exacerbation in the first 2 years, 74% also had no exacerbation in year 3. The data from the ECLIPSE study suggest an exacerbation-susceptibility phenotype, in which patients are prone to exacerbations as a result of intrinsic susceptibility and have exacerbations based on exposure to particular triggers. The study also found that 22% of patients with moderate COPD had frequent exacerbations, suggesting an overall greater burden of exacerbation with milder disease, while 29% of patients with very severe COPD appeared to have resistance to exacerbations. One of the key takeaway points from this study is that we should have a heightened awareness that this frequent exacerbation-susceptibility phenotype exists for many of our patients with moderate COPD. It is essential that we do a good job when taking a history making sure to ask about the number of exacerbations patients have had in the past year.

Last week, the Lancet published two articles from the Swedish Systolic Heart failure treatment with the If inhibitor Ivabradine Trial (SHIFT). SHIFT is a randomized, double-blinded, placebo-controlled, parallel-group study designed to evaluate the effect of heart-rate reduction by Ivabradine on outcomes in heart failure.[9] Ivabradine is a specific inhibitor of the If current in the sinoatrial node and does not act on other channels in the heart or vascular system. This was a large RCT that analyzed the data for 3241 patients assigned to the Ivabradine arm compared to 3264 patients receiving placebo. The first study reported a slight difference in the number of patients on Ivabradine (24%) who had a primary endpoint event of cardiovascular death or hospital admission for worsening heart failure compared to 29% from the placebo group. There were significantly fewer admissions for worsening heart failure in the Ivabradine group (16%) versus the placebo arm, as well as for deaths due to heart failure. The main adverse events for Ivabradine group were symptomatic bradycardia (5% vs 1% in placebo group) and visual side-effects of transient enhanced brightness in a restricted area of the visual field (3% vs 1%, p<0.001). Overall, the authors noted an important benefit from heart-rate reduction with Ivabradine in improving clinical outcomes in heart failure. The second article produced from SHIFT in this week’s Lancet addressed the hypothesis that baseline heart rate and heart rate reduction could improve cardiovascular outcomes in heart failure.[10] In this particular analysis, the investigators analyzed the heart rate achieved at 28 days on Ivabradine and its relationship to subsequent clinical outcomes. The findings from this analysis showed that patients in the placebo group with a higher heart rate at baseline (≥87 beats per minute) were at more than a two-fold greater risk for a primary endpoint than those patients with lower heart rates, a difference that was signficant. The Ivabradine group demonstrated that patients with lower heart rates (<60 bpm) at the 28 days of treatment had fewer primary composite endpoint events when compared to the patients with higher heart rates. In patients with heart failure who were in normal sinus rhythm at heart rates ≥ 70 bpm, there was a continuous direct association between baseline heart rate and outcomes. The risk is significantly modified and reduced by Ivabradine, which had a greater effect on patients with higher baseline heart rate values and corresponding greater heart rate reduction. Because the clinical outcomes improved in patients with lower heart rates on Ivabradine, the authors concluded that selective lowering of heart rates with Ivabradine can improve cardiovascular outcomes and that heart rate reduction is an important target in treating heart failure. Since this is an RCT conducted in Sweden, it is hard to determine if Ivabradine will receive FDA approval in the near future and how much this research will impact us in the U.S. However, we can learn from these studies that heart rate reduction is an important component when caring for our patients with chronic heart failure, and that newer drugs designed to specifically for the purpose of heart rate reduction are in the pipeline.

Dr.  Dong is a first year resident at NYU Langone Medical Center

Peer Reviewed by Danise schiliro, MD  Contributing Editor, Clinical Correlations


[1]  Pollack A. FDA Panel Urges Denial of Diet Drug. The New York Times 2010.

[2]  Richwine L. U.S. advisers reject Arena diet drug., September 16, 2010.

[3]  Melnick M. New Fat Fighting Machines: Real, FDA Approved. Time Magazine. September 15, 2010.

[4]  Chen PW. Teaching Doctors About Nutrition and Diet. The New York Times 2010.

[5] Ofri D. What makes a good doctor? Can we measure it?  CNN Health. September 16, 2010.

[6]  Hong CS, Atlas SJ, Chang Y, Subramanian SV, Ashburner JM, Barry MJ, Grant RW. Relationship between patient panel characteristics and primary care physician clinical performance rankings. JAMA 2010; 304(10): 1107-1113.

[7]  Mamede S, van Gog T, van den Berge K, Rikers RMJP, van Saase JLCM, van Guldener C, Schmidt HG.  Effect of availability bias and reflective reasoning on diagnostic accuracy among internal medicine residents. JAMA 2010; 304 (11): 1198-1203.

[8]  Hurst JR, Vestbo J, Anzueto A, Locantore N, Mullerova H, Tal-Singer R, et al. Susceptbility to exacerbation in chronic obstructive pulmonary disease. The New England Journal of Medicine 2010; 363 (12): 1128-1138.

[9] Swedberg K, Komajda M, Bohm M, Borer JS, Ford I, Dubost-Brama A, et al. Ivabradine and outcomes in chronic heart failure (SHIFT): a randomized placebo-controlled study. The Lancet 2010; 376 : 875-885.

[10]  Bohm M, Swedberg K, Komajda M, Borer JS, Ford I, Dubost-Brama A, et al. Heart rate as a risk factor in chronic heart failure (SHIFT): the association between heart rate and outcomes in a randomized placebo-controlled trial.  The Lancet 2010; 376: 886-894.

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