Primecuts – This Week In the Journals

August 30, 2016

PrimeCuts 8 min read

zikaBy Nancyanne Schmidt, MD

Peer Reviewed

As we enter the final weeks of summer, the peril posed by the tiny mosquito continues to grow to shark-sized proportions. The FDA now recommends that all blood donations in the U.S. be screened for the Zika virus, after the agency had earlier advised only testing in areas with an active outbreak [1]. The FDA is recommending blood facilities in eleven states, including New York, to begin testing for Zika in the next four weeks.

On the other side of the Atlantic, many Europeans are enjoying the August holiday on the beach – but not without some controversy. On Friday, France’s highest administrative court overturned the ban on “burkinis” in the town of Villeneuve-Loubet [2]. Burkinis are full body swimwear worn by some Muslim women. The ruling made clear that such a ban violated civil liberties, including freedom of movement and religious freedom.

Meanwhile in the U.S., Colin Kaepernick became the most recent celebrity to take a stand for civil rights. The San Francisco 49ers quarterback became the latest in a string of high profile athletes who have used their platform to speak out about racism, civil rights issues and gun violence [3]. Kaepernick refused to stand during the national anthem before a game on Friday, protesting the treatment of racial minorities in the U.S.

From the latest and breaking news from around the world, we now look at the journal articles that have made headlines this week:

70-Gene Signature as an Aid to Treatment Decisions in Early-Stage Breast Cancer

Breast cancer is the most frequently diagnosed cancer in women and the leading cause of cancer death in women as well. Deciding to treat patients with adjuvant chemotherapy is based on tumor grade, size, nodal involvement, hormonal receptor status and individual characteristics such as age and performance status. However, since treatment decision algorithms often do not take into account individual genetic characteristics of tumors, it is reasonable to assume that a substantial number of patients with breast cancer may be receiving adjuvant chemotherapy unnecessarily. Using gene expression studies to analyze the unique genetic characteristics of breast tumors may be useful in deciding whether adjuvant chemotherapy is an appropriate treatment for each patient.

A study published this week in the New England Journal of Medicine used one such test, the 70-gene signature Mamma-Print, in addition to standard clinico-pathological data to select patients who would specifically benefit from adjuvant chemotherapy [4]. This international, prospective, randomized, phase 3 study examined five-year outcomes among 1550 breast cancer patients with high-risk clinical features but a low-risk gene-expression profile. Of these patients with discordant risk group analyses, 749 were assigned to receive chemotherapy, while 748 did not receive adjuvant chemotherapy. The aim was to assess whether patients with high-risk clinical features but a low-risk gene-expression profile could achieve the primary endpoint of 92% survival at five years. The five-year survival without distant metastasis was 94.7% (95% CI, 92.5 – 96.2%), which established noninferiority.

In the discordant group that did receive chemotherapy, the five year survival rate without distant metastasis was 1.5% higher in comparison with patients who did not receive adjuvant chemotherapy — 95.9% vs 94.4%. The study was not powered to assess the statistical significance of these differences but the magnitude of chemotherapy benefit appears modest when considering its cost, inconvenience and associated risks.

This study proves that it is possible to identify patients who may not benefit from adjuvant chemotherapy, although how patients and clinicians interpret the results of genetic tests in addition to clinical risk prognosticators will remain highly individualized.

Association of Integrated Team-Based Care With Health Care Quality, Utilization, and Cost

The benefits of patient care in team-based settings that combine mental health and primary care teams have been praised, but additional evidence of its utility in a large healthcare delivery system is still needed.

In a study published this week in The Journal of the American Medical Association, researchers sought to evaluate the outcomes of receiving care in integrated team-based practices vs traditional management practices [5]. This retrospective, longitudinal, cohort study assessed quality, hospital utilization and cost outcomes associated with receipt of primary care in team based practices. Since the year 2000, Intermountain Healthcare, a healthcare delivery system based in Utah and Idaho, has incorporated the use of physical and mental health teams in family medicine, pediatric and internal medicine primary care clinics. 113,452 unique adult patients from 113 Intermountain Medical group primary care practices were studied from January 2010 to December 2013, and these patients treated via Intermountain Healthcare team based care (TBC) were compared with those treated in traditional practices (TPM). Patients treated in the team based care model had higher rates of adherence to a diabetes care plan (24.6% for TBC vs 19.5% for TPM; odds ratio [OR] 1.26 [95%CI, 1.11 to 1.42]), active depression screening (46.1% for TBC vs 24.1% for TPM; OR 1.91 [95% CI, 1.75 to 2.08]), and documentation of self-care plans (48.4% for TBC vs 8.7% for TPM; OR 5.59 [95% CI, 4.27 to 7.33]). Of note, the TBC group had a lower proportion of patients with controlled hypertension (defined as <140/90 mmHg) – 85.0% for TBC vs 97.7% for TPM (OR 0.87 [95%CI, 0.80 to 0.95]). Rates of healthcare utilization were lower for patients in the TBC group including average number of emergency department visits (18.1 for TBC vs 23.5 for TPM; incidence rate ratio [IRR] 0.77 [95%CI, 0.74 to 0.80]), and average number of hospital admissions (9.5 for TBC vs 10.6 for TPM; IRR 0.89 [95%CI, 0.85 to 0.94]).

This study clearly demonstrates that in a team based care setting there can be improved quality of care for patients with depression and diabetes as well as reductions in some measures of acute care utilization. There are several drawbacks to this study, including but not limited to, the fact that Intermountain healthcare is a fully integrated delivery system, so direct translation of these results may be limited in settings without a similar support infrastructure.

A Placebo-Controlled Trial of Obeticholic Acid in Primary Biliary Cholangitis

Primary biliary cholangitis is characterized by T-lymphocyte mediated attack on interlobular epithelial bile duct cells leading to their destruction. The resultant cholestasis can lead to eventual cirrhosis, end-stage liver disease and death. Treatment with ursodeoxycholic acid delays progression to end stage liver disease as well as time to liver transplantation, however there is an unmet need for additional therapy options in PBC patients with persistent elevated alkaline phosphatase levels despite ursodiol treatment, as well as patients unable to tolerate treatment. Obeticholic acid (OCA), a farnesoid X receptor ligand agonist, impairs bile acid synthesis and stimulates choleresis, presenting a viable alternative for PBC patients [6]. In prior placebo controlled trials, obeticholic acid resulted in significantly greater decreases in alkaline phosphatase and bilirubin compared to placebo, but also demonstrated dose-related increases in the incidence and severity of pruritus [7].

A study published in The New England Journal of Medicine sought to assess the longer-term efficacy, safety, and adverse-event profile of obeticholic acid in patients with primary biliary cholangitis who were receiving daily doses of 5mg or 10mg [8]. In this double-blind, placebo- controlled, parallel-group, 12-month phase 3 trial, 216 patients (91% women, 94% white) were assigned to either receive placebo (N=73), obeticholic acid 5mg with an increase to 10mg after six months (N=70), or obeticholic acid 10mg (N=73), all of which were added to standard of care ursodiol 13-15mg/kg. The primary endpoints were an alkaline phosphatase level less than 1.67 times the upper limit of the normal range with a reduction of at least 15% from baseline, and a total bilirubin level at or below the upper limit of the normal range at 12 months. 46% of patients in the 5–10-mg group and 47% of patients in the 10-mg group achieved these endpoints compared to just 10% of those in the placebo group (P<0.001 for both comparisons). These effects were sustained for two years. Non-invasive measures of liver fibrosis, elastography and enhanced liver fibrosis score did not differ between either treatment group and the placebo group.  Pruritus was the most common adverse event across all groups (56% of patients in the 5–10-mg group and 68% of those in the 10-mg group vs. 38% in the placebo group).

This study demonstrates that treatment with obeticholic acid results in improvement in biochemical markers of disease in patients with inadequate response to or inability to tolerate ursodiol. Since this study examined patients for two years, it is unclear if obeticholic acid improve outcomes such as survival. This study cohort is part of a multiyear study to assess the effects of obeticholic acid on clinical outcomes in patients with primary biliary cholangitis who have more advanced liver disease.

Nonrandomized Intervention Study of Naloxone Coprescription for Primary Care Patients Receiving Long-Term Opioid Therapy for Pain

The United States is in the midst of an opioid overdose epidemic, with the death rate increasing from 1.4 per 100,000 adults in 1999 to 5.4 per 100,000 adults in 2011 [9]. Supplying those likely to experience or witness an overdose with naloxone has been associated with reductions in opioid overdose mortality [10]. However, literature to support prescription of naloxone in primary care settings is limited to anecdotes and early descriptive analyses.

A study published in the Annals of Internal Medicine aimed to better understand the feasibility of prescribing naloxone for patients already receiving opioid medications [11]. In this 2-year, nonrandomized intervention study conducted at six primary care clinics in San Francisco, 1985 adults receiving long-term opioid therapy were identified as candidates to receive naloxone. Naloxone was prescribed to 759 patients, or 38.2% of eligible clinic patients. Patients receiving higher opioid doses were more likely to be prescribed naloxone (adjusted odds ratio 1.73 [CI, 1.57 to 1.92]; P<0.001) as were those patients who were seen in the county Emergency Department for an opioid-related visit in the 12 preceding months (adjusted odds ratio 2.54 [CI, 1.54 to 4.18]; P<0.001). In the six months after receipt of the prescription, patients who received naloxone had 47% fewer opioid related ED visits per month (IRR, 0.53 [CI, 0.34 to 0.83]; P = 0.005) and a 63% reduction after 1 year (IRR, 0.37 [CI, 0.22 to 0.64]; P < 0.001) compared with those who did not receive a prescription. Limitations of this study include the lack of data to confirm that patients filled their naloxone prescriptions. It is also possible that patients received care outside of the safety net system. Lastly, causality cannot be inferred from this observational study.

This study demonstrated that when clinicians are properly advised, naloxone can be co-prescribed to primary care patients receiving opioids for pain with the ancillary benefit of reducing opioid related adverse events.

MINI CUTS

In a randomized trial, researchers found that MRI guided thalotomy improved hand tremor scores in patients with essential tremor [12]. This study provided the basis for the recent FDA approval of the first focused ultrasound device (ExAblate Neuro, InSightec) to treat essential tremor.

A retrospective study of men with prostate cancer showed that adding radiation to androgen-deprivation therapy improved survival [13].

The largest randomized trial to date comparing drug eluting stents to bare metal stents found similar outcomes with each stent at 6 years[14]. Drug eluting stents had lower rates of restenosis and thrombosis.

Dr. Nancyanne Schmidt is a 1st-year resident at NYU Langone Medical Center.

Peer reviewed by Dr. Amar Parikh, 3rd year internal medicine resident at NYU Langone Medical Center

Image courtesy of www.inhabitat.com

References

  1. St. Louis Catherine. All Donated Blood in U.S. Should Be Tested for Zika, F.D.A. Says. NY Times [New York] 26Aug16. http://www.nytimes.com/2016/08/27/science/all-donated-blood-in-us-will-be-tested-for-zika.html?_r=0
  2. Breeden, Aurelien and Blaise, Lilia. Court Overturns ‘Burkini’ Ban in French Town. NY Times [New York] 26Aug16. http://www.nytimes.com/2016/08/27/world/europe/france-burkini-ban.html
  3. Reilly, Katie. Colin Kaepernick Protests National Anthem Over Treatment of Minorities: ‘There Are Bodies in the Street’. Time Magazine, 26Aug16
  4. Cardoso F et al. 70-Gene Signature as an Aid to Treatment Decisions in Early-Stage Breast Cancer, N Engl J Med 2016 Aug 25; 375:8 http://www.nejm.org/doi/full/10.1056/NEJMoa1602253
  5. Reiss-Brennan B, Brunisholz KD, Dredge C, et al. Association of Integrated Team-Based Care With Health Care Quality, Utilization, and Cost [published online August 23/30, 2016]. JAMA. 2016;316(8):826-834.  http://jama.jamanetwork.com/article.aspx?articleid=2545685&linkId=27731181
  6. Carbone M, Mells GF, Pells G, et al.Sex and age are determinants of the clinical phenotype of primary biliary cirrhosis and response to ursodeoxycholic acid. Gastroenterology 2013; 144(3): 560-569
  7. Hirschfield GM, Mason A, Luketic V, et al. Efficacy of obeticholic acid in patients with primary biliary cirrhosis and inadequate response to ursodeoxycholic acid. Gastroenterology 2015; 148(4): 751- 61
  8. Nevens F et al. A placebo-controlled trial of obeticholic acid in primary biliary cholangitis. N Engl J Med 2016 Aug 18; 375:631 http://www.nejm.org/doi/full/10.1056/NEJMoa1509840?af=R&rss=currentIssue
  9. Chen LH, Hildegard H, Warner M. Drug-poisoning deaths involving opioid analgesics: United States, 1999-2011. NCHS data brief, no166. Hyattsville, MD: National Center for Health Statistics; 2014.  http://www.cdc.gov/nchs/products/databriefs/db166.htm
  10. Walley AY, Xuan Z, Hackman HH, Quinn E, Doe-Simkins M, Sorensen-Alawad A, et al. Opioid overdose rates and implementation of overdose education and nasal naloxone distribution in Massachusetts: interrupted time series analysis. BMJ. 2013;346:f174. [PMID: 23372174] doi:10.1136/bmj.f174
  11. Coffin PO, BeharE, Rowe C,et.al. Nonrandomized Intervention Study of Naloxone Coprescription for Primary Care Patients Receiving Long-Term Opioid Therapy for Pain.Ann Intern Med. 2016;165:245-252 http://www.ncbi.nlm.nih.gov/pubmed/27366987
  12. Elias,WJ, et.al. A Randomized Trial of Focused Ultrasound Thalamotomy for Essential Tremor. N Engl J Med 2016; 375:730-739
  13. Rusthoven CG, Jones BL, Flaig TW, et al: Improved survival with prostate radiation in addition to androgen deprivation therapy for men with newly diagnosed metastatic prostate cancer. J Clin Oncol 34:2835-2842, 2016
  14. Bønaa KH et al. Drug-eluting or bare-metal stents for coronary artery disease. N Engl J Med 2016 Aug 30; http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3072800/