Primecuts – This Week In The Journals

October 1, 2012

By Joseph Marsano, MD

Faculty Peer Reviewed

This past week marked the meeting of the UN general assembly and with it the resultant heavy traffic stagnating much of east side Manhattan. The topic on everyone’s mind was the impact of Iran’s pursuit of nuclear technology on the relationship between the United States and Israel. As this topic grabbed much of the headlines, and rightfully so, there was less attention paid to the large widening gap between much of the industrialized world and developing nations when it comes to health. A recent article was published in Lancet advocating for a global campaign against epilepsy[1]. 85% of the global burden of epilepsy is found in low-income/developing countries directly caused by the lack of accessible anti-epileptic drugs. Complicating this issue, the risk factors of epilepsy in these countries are often preventable. They arise from antenatal and perinatal complications, and parasitic diseases such as toxoplasmosis, neurocysticercosis, onchocerciasis, malaria, and toxocariasis. Epilepsy carries a high disease burden when left untreated and a concerted effort to increase access to anti-epileptic drugs would bring about a cost-effective solution.

As we move closer to home, cancer continues to be one of the leading causes of death in the USA. This week a new drug was approved by the FDA that has shown a survival benefit in patients with metastatic colon cancer [2]. The drug, Regorafenib (Stivagra), is an orally active diphenylurea multikinase inhibitor of VEGFR1-3. It was approved by the FDA based on a recent study showing that overall survival was 6.4 months compared to 5 months in placebo group (HR 0.77 p = 0.0102). Though this is a small improvement, it does provide some survival benefit to those patients with metastatic colorectal cancer that are refractory to current FOLFIRI regimen. In related news, a study was published this week in the New England Journal of Medicine that looked at whether Enzalutamide, an inhibitor of multiple steps in the androgen signaling pathway, could prolong survival in men with castration resistant prostate cancer after chemotherapy [3]. This was a double-blind placebo controlled trial that included 1199 participants who were randomly assigned in a 2:1 ratio to receive Enzalutamide 160 mg daily vs placebo with survival as a primary end-point. The median overall survival in the Enzalutamide group was 18.4 months versus 13.6 months (HR 0.63, p < 0.001). In addition, those in the treatment group showed greater reductions in prostate-specific antigen (54% vs. 2% p < 0.001), quality of life (29% vs 4% p < 0.001), and radiographic progression-free survival (8.3 vs. 2.9 months p <0.001). Both of these anti-tumor medications provide modest survival benefit compared to placebo and in the case of Enzalutamide a significant reduction in adverse events compared to placebo resulting in more pronounced quality of life.

Moving on, a phase IIb study in the Journal of the American College of Cardiology looked at Beta-receptor blockade in isolated chronic degenerative mitral valve regurgitation (MR) [4]. There is no current medical therapy for isolated MR. When MR becomes severe enough leading to left ventricular (LV) dysfunction, LV remodeling and eventually heart failure, the treatment is surgical mitral valve replacement. In heart failure, beta-blockers have been shown to improve LV function and LV remodeling. This current study aimed to see whether similar benefits of beta-blockers extend to patients with asymptomatic moderate-to-severe MR. 38 patients were included in the study and randomly assigned to receive beta-blocker or placebo for 2 years. MRI tissue tagging and 3-D dimensional analysis was done at baseline and 6-month intervals over the 2 year period. The primary end-points included: LV end-diastolic volume, LV ejection fraction, LV end-diastolic (ED) mass/ED volume ratio, LV wall thickness, LV end-systolic volume, LV longitudinal strain rate, and LV early diastolic filling rate. At baseline there was no statistical difference between the groups; however at 2 years there was statistical difference with respect to LV EF . Based on the slopes between the treatment group and placebo, EF was expected to decrease by as much as 1.92% and as much as 7.92% compared to the treatment group (p = .006). This at least points to the idea that beta blockers can stabilize ejection fractions compared to placebo. Importantly, this is the first study that shows a benefit of medical treatment for MR and could become standard practice if similar benefits are shown in a larger multi-centered study.

Switching gears from clinical trials, in Academic Medicine, a recent study in Italy looked at the relationship between physician empathy and disease complications –specifically diabetics [5]. To measure the level of physician empathy, researchers used a validated Jefferson Scale of Empathy (JSE) – 20 item questionnaire on a 7 point scale (1-strongly disagree to 7-strongly agree) – that evaluates perspective taking, compassionate care and “walking in the patients’ shoes.” The study was carried out within the local health authority in Parma, Italy in conjunction with researchers at Jefferson Medical College. 242 physicians completed the evaluation (80.4% response rate) and patients who were enrolled with any of the participating physicians during 2009 were included. A total 20,961 patients that had primary or secondary ICD-9-CM codes indicating diabetes mellitus or prescriptions that included insulin, insulin analogues or glucose-lowering drugs were identified. Primary end-point was hospitalization for acute metabolic complications (DKA, hyperglycemia, coma) during 2009. There was about equal distribution of physicians within three groups: high, moderate and low scorers on the JSE. The rate of acute hospitalizations per 1,000 patients was 4.0, 7.1, and 6.5 with high, moderate and low scorers, respectively. The difference between high and low/moderate scorers was statistically significant; however there was no statistical significance between moderate and low scorers. These results on the surface indicate a correlation between empathy and healthcare outcomes. As medical education evolves, there should continue to be a strong focus on physician-patient interactions, as this will increase patient satisfaction while possibly decreasing complication rates.

We have all learned about the relationship between cardio-pulmonary fitness and healthy aging. In the Archives of Internal Medicine, a recent study was published that looked at cardio-pulmonary fitness in healthy, middle age adults and its relationship to development of chronic health conditions: congestive heart failure, ischemic heart disease, stroke, diabetes mellitus, chronic obstructive pulmonary disease, chronic kidney disease, Alzheimer disease, and colon or lung cancer [6]. 18,670 participants were studied using participant data from the Cooper Center Longitudinal Study and cross-referenced with Medicare coverage claims between 1999-2009. Fitness was estimated using a Balke treadmill time when they enrolled in the study and analyzed as a continuous variable based on sex and age-specific quintiles. Participants were adjusted for age, BMI, blood pressure, cholesterol and glucose levels, alcohol and smoking. Both men and women who had a higher fitness level (quintile 5) had a lower incidence of chronic conditions compared to those with the lowest (quintile 1) (15.6 vs 28.2 per 100 person years in men, and 11.4 vs 20.1 per 100 person years in women). Since many of these chronic conditions carry with them high morbidity and mortality in older age, it is clear that mid-life fitness should be just as important as pharmacologic risk factor reduction in middle age patients.

Some other articles that garnered attention this week:

i. Delirium and Long-term Cognitive Trajectory Among Persons With Dementia http://archinte.jamanetwork.com.ezproxy.med.nyu.edu/article.aspx?articleid=1351352

This study looked at the deleterious effects of delirium in patient’s with Alzheimer’s Disease (AD). They found that patient’s with AD who were hospitalized and developed delirium had increased cognitive decline with effects lasting up to 5 years. Given the high prevalence of delirium in hospitalized patients, it is important to prevent it in patients with AD.

ii. Thalidomide for the Treatment of Cough in Idiopathic Pulmonary Fibrosis: A Randomized Trial http://annals.org/article.aspx?articleid=1359219

When we hear about Thalidomide, we often think about birth defects. However, in this single-center study, Thalidomide reduced cough and improved respiratory quality of life in patients with idiopathic pulmonary fibrosis.

iii. Tiotropium in Asthma Poorly Controlled with Standard Combination Therapy http://www.nejm.org/doi/full/10.1056/NEJMoa1206044

In this study, poorly controlled asthmatics benefitted from the addition of Tiotropium to inhaled glucocorticoids and long-acting beta-agonists. It prolonged the time to first severe exacerbation and provided modest sustained bronchodilation compared to placebo.

iv. Choice of Initial Combination Antiretroviral Therapy in Individuals With HIV Infection: Determinants and Outcomes  http://archinte.jamanetwork.com/article.aspx?articleid=1309577

This article looked at differences in initial prescriptions of anti-retroviral medications and found that much of them centered on physician preference and patient characteristics. It argues that more evidence-based data is needed to determine the best initial regimens.

Dr. Joseph Marsano is a 1st year resident at NYU Langone Medical Center

Peer reviewed by Neil Shapiro, MD, Editor-In-Chief, Clinical Correlations

Image courtesy of Wikimedia Commons

References:

1. Wanted: a global campaign against epilepsy.The Lancet.29 September 2012 (Volume 380 Issue 9848 Page 1121)  http://www.thelancet.com/journals/lancet/article/PIIS0140-6736(12)61646-8/fulltext?rss=yes

2.  http://www.accessdata.fda.gov/drugsatfda_docs/label/2012/203085lbl.pdf

3. Scher, H.I et al. Increased Survival with Enzalutamide in Prostate Cancer after Chemotherapy. New England Journal of Medicine. 367:1187-1197, 2012 http://www.nejm.org/doi/full/10.1056/NEJMoa1207506

4. Ahmed, M.I. et al. A Randomized Controlled Phase IIb Trial of Beta1-Receptor Blockade for Chronic Degenerative Mitral Regurgitation. Journal of the American College of Cardiology. (Vol 60, Issue 9, 833-838, 2012). http://content.onlinejacc.org/article.aspx?articleid=1221476

5. Del Cannale, S et al. The Relationship Between Physician Empathy and Disease Complications: An Empirical Study of Primary Care Physicians and Their Diabetic Patients in Parma, Italy. Academic Medicine. 87: 1243-1249, 2012.

6.  Willis, BL et al. Midlife Fitness and the Development of Chronic Conditions Later in Life. Archives of Internal Medicine. 172: 1333-1340, 2012.  http://archinte.jamanetwork.com/article.aspx?articleid=1352789

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