Primecuts – This Week In The Journals

January 9, 2017

PrimeCuts 8 min read

primecuts 1.9.17By: Nancyanne Schmidt, MD

Peer Reviewed

This week, the intelligence report commissioned by President Obama on suspected hacking during the recent presidential election revealed that Russian President Vladimir Putin ordered an influence campaign [1] aimed at undermining The Democratic National Committee and Hillary Clinton’s campaign, in particular. The report, which compiled the collective assessments of the C.I.A., National Security Agency and F.B.I., stopped short of implicating Russia in the outcome of the recent presidential election in which President-elect Donald Trump defeated Hillary Clinton in a stunning victory.

In other political news, Michelle Obama delivered her final farewell on Friday, during an event for school counselors where she encouraged young people to remain focused and determined. “That’s my final message to young people as first lady,” Mrs. Obama said, as many in the audience applauded and became teary-eyed. “Lead by example with hope, never fear. And know that I will be with you, rooting for you and working to support you for the rest of my life.” [2]

With the hopeful words of our (soon-to-be former) First Lady in mind here are some of the recent scientific advances that have made the news this week:

Cardiovascular safety of Celecoxib, Naproxen, or Ibuprofen for arthritis

Previous studies have described the increased risk of adverse cardiovascular events in patients taking 400 mg to 800 mg daily doses of the cyclooxygenase (COX)-2 inhibitor celecoxib [3]. At more moderate doses, however, the safety of celecoxib remains to be characterized. In a randomized double blind trial of 24,081 patients with osteoarthritis or rheumatoid arthritis and elevated cardiovascular risk [4], researchers compared celecoxib (100 mg twice daily), naproxen (375 mg twice daily), and ibuprofen (600 mg three times daily). The goal of the trial was to assess if celecoxib was non-inferior to naproxen and ibuprofen with regards to the composite primary outcome of cardiovascular death, nonfatal myocardial infarction, or nonfatal stroke. The primary outcome occurred in 2.3% of the celecoxib group, 2.5% of the naproxen group, and 2.7% of the ibuprofen group (HR for celecoxib vs. naproxen, 0.93; 95% confidence interval [CI], 0.76 to 1.13; HR for celecoxib vs. ibuprofen, 0.85; 95% CI, 0.70 to 1.04; P<0.001). The risk of gastrointestinal events was lower in the celecoxib group when compared with the naproxen group (HR 0.71; 95% CI, 0.54 to 0.93, P=0.01) and the ibuprofen group (HR 0.65; 95% CI, 0.50 to 0.85, P=0.002). This trial provides compelling evidence that at moderate doses, celecoxib is not associated with more cardiovascular risk than two widely used nonselective NSAIDs, naproxen and ibuprofen. Cardiovascular safety of higher dose of celecoxib compared to other NSAIDs remains unclear from this study.  During the trial, 68.8% of the patients stopped taking the study drug and 27.4% discontinued follow-up. High levels of loss to follow up-for all three treatments make interpreting the findings of this study challenging.

Effect of immediate initiation of ART on risk of severe bacterial infections

In patients newly diagnosed with HIV and high CD4 counts, immediate initiation of antiretroviral therapy (ART) is known to induce viral suppression and reduce the risk of AIDS and non-AIDS related morbidity and mortality [5]. However, the impact of immediate ART initiation on the risk of bacterial infections is not well described in the literature. As part of the INSIGHT START study group, Jemma O’Connor and colleagues sought to assess [6] the effects of immediate versus deferred ART initiation in 4,685 HIV positive participants with CD4 count over 500 cells/µL. Of the 4,685 HIV positive patients, who were followed for a median of 2.8 years in 35 countries, 2,326 were randomly assigned to begin antiretroviral therapy immediately. Compared to patients assigned to deferred ART initiation, those randomly assigned to immediate ART initiation had a reduced risk of severe bacterial infections (HR 0.39, 95% CI 0.26–0.57, p<0.0001) such as bacterial pneumonia, pulmonary tuberculosis and extra pulmonary tuberculosis. Over the course of the follow up period, the average CD4 cell count in the immediate ART initiation group was 194 cells/µL higher than the deferred initiation group (p<0.0001). These findings demonstrate that early initiation of ART has a protective effect on immune function and provide further evidence of the benefits afforded by early ART initiation including viral suppression, reduced risk of transmission, and increased CD4 cell count.

Types of myocardial infarction among HIV-infected individuals in the United States

Studies have suggested that rates of myocardial infarctions(MIs) in HIV infected individuals may be higher when compared with those not infected [7,8]. HIV may cause endothelial dysfunction and dyslipidemia while some antiretroviral agents may contribute to increased cardiovascular disease risk. Previous studies examining cardiovascular disease in HIV positive individuals have not characterized the frequencies and types of MIs. A better understanding of both factors is important in determining if prognosis and medical management of MIs differ in this population. A longitudinal study published this week in JAMA Cardiology [9] sought to characterize MIs in HIV positive individuals by type and frequency. Myocardial Infarctions were classified according to The Second Universal Definition of Myocardial Infarction, which divides MIs into five types including type 1, which result from spontaneous instability of an atherosclerotic plaque, and type 2, which occurs in the setting of an oxygen supply-demand mismatch. In the 571 HIV positive patients identified with a definite or probable MI, researchers found that 49.6% had a type 1 MI and 50.4% had a type 2 MI. The most common causes of type 2 MIs in the study were sepsis/bacteremia (34.7% of type 2 MIs) and illicit drug related vasospasm (13.5% of type 2 MIs). Patients who had type 2 MIs had lower CD4 counts (median, 230 vs 383 cells/µL, p=0.02), lower cholesterol levels (mean [SD] total cholesterol level, 167 [63] vs 190 [54] mg/dL, p<0.001), and lower Framingham risk scores (8% vs 10%, p<0.001) when compared to patients who had type 1 MIs. Those who had type 2 MIs had fewer traditional cardiovascular disease risk factors as evidenced by their lower cholesterol levels and Framingham risk scores and were more likely to be younger than 40 years old (47 of 288 [16.3%] vs 32 of 362 [8.8%]).

While type 1 and 2 MIs occur at about equal frequency in HIV infected patients, each type of MI affects different subgroups of HIV patients. Specifically, type I MIs are related to traditional ASCVD risk factors that are not unique to HIV patients, and type 2 MIs appear to be related to severity of HIV-induced immunosuppression and the resultant increased risk of sepsis. This study illuminates the fact that more research is needed to better characterize the association between HIV and specific CVD risk factors, as well as if different types of MI require different approaches for treatment and prevention in this population. 

A proposed Trastuzumab biosimilar for treatment of ERBB2 (HER2)-positive metastatic breast cancer

Treatment with Trastuzumab (Herceptin) for ERBB2 positive breast cancer greatly improves progression free survival and overall survival. Like other biologic agents, access to Trastuzumab is limited in many countries, although it is listed on the World Health Organization’s list of essential cancer medications [10]. Unlike other drugs, biologic agents are made in living cells, extracted and purified. For this reason, development of biosimilar compounds requires specific testing to be sure that they are comparable to their more expensive patented counterparts. If clinically comparable to a known biologic agent, a biosimilar agent could encourage market competition and lower prices for valuable biologic treatments.  To this end, a recent study examined the response rate and overall safety of trastuzumab plus a taxane versus a trastuzumab biosimilar plus a taxane in treatment naive patients with metastatic ERBB2 positive breast cancer [11]. In this multicenter double-blind, randomized study 228 women were treated with trastzumab plus a taxane and 230 women were treated with the trastuzumab biosimilar plus a taxane. The overall response rate at 24 weeks of treatment was 69.6% (95% CI, 63.62%-75.51%) for the proposed biosimilar vs 64.0% (95% CI, 57.81%-70.26%) for trastuzumab.  Overall response rate was defined as partial or complete response according to RECIST criteria, which define complete response as tumor disappearance and partial response as more than 30% decrease in size on CT or MRI [12].  In comparing treatment related adverse events, there were no notable differences between the two treatment groups. This study’s confirmation of the equal efficacy of trastuzumab and the proposed biosimilar is a crucial step forward in expanding access to biologics. Ongoing study follow-up will compare long term efficacy and safety as well as use of the trastuzumab biosimilar during maintenance therapy.

This week’s Mini-cuts:

A study published in The Lancet last week [13] tracking all adults between the ages of 20 and 85 living in Ontario, Canada between 2001 and 2012 demonstrated a 7% increased risk of being diagnosed with dementia in those people who lived 50 meters or closer to major roads. Researchers hypothesize that the increase may be attributed to environmental stressors or increased air pollution exposure.

A study examining the gut microbiome [14], the bacteria and microbes that live in the intestinal tract, found that humans who ate a calorie restricted, plant-based diet had a more diverse array of gut bacteria richer in beneficial strains of bacteria. When these gut bacteria were transplanted into mice who were then fed healthy versus unhealthy diets, the mice who were transplanted with the richer gut microbiomes were able to diversify their gut microbial communities to a much greater extent compared to mice who received microbiome transplants from humans used to unhealthy, calorie-rich diets. The study suggests that diet can have a profound effect on the gut microbial community, in turn effecting the way our bodies are able to process food.

A study published this week sought to assess the relationship between a Mediterranean type diet (a diet rich in fruits, vegetables, cereals, olive oil, moderate consumption of fish, and low intake of red meat) on brain structural aging. The study found that participants who adhered more closely to the Mediterranean diet had less total brain atrophy and greater cortical thickness [15].

Dr. Nancyanne Schmidt is a 1st year internal medicine resident, NYU Langone Medical Center

Peer reviewed by Ian Henderson, MD, 3rd year internal medicine resident at NYU Langone Medical Center

Image courtesy of Chip Somodevilla/Getty Images

References

  1. Sanger, DE. Putin Ordered ‘Influence Campaign’ Aimed at U.S. Election, Report Says. nytimes.com January 6,2017
  2. Horseley, S. Michelle Obama’s Emotional Farewell: ‘The Power Of Hope’ Has ‘Allowed Us To Rise. npr.org January 6,2017
  3. Solomon SD, McMurray JJV, Pfeffer MA, et al. Cardiovascular risk associated with celecoxib in a clinical trial for colorectal adenoma prevention. N Engl J Med 2005;352:1071-1080
  4. Nissen SE, Yeomans ND, Solomon DH, et.al. Cardiovascular Safety of Celecoxib, Naproxen or Ibuprofen for Arthritis. N Engl J Med 2016; :2519-2529 December 29, 2016 DOI: 10.1056/NEJMoa1611593
  5. Pilcher CD, Ospina-Norvell C, Dasgupta A, et al. The effect of same-day observed initiation of antiretroviral therapy on HIV viral load and treatment outcomes in a U.S. public health setting. J Acquir Immune Defic Syndr. 2016 Jul 16.
  6. O’Connor, J, Vjecha, MJ, Phillips, AN et al. Effect of immediate initiation of antiretroviral therapy on risk of severe bacterial infections in HIV-positive people with a CD4 cell count of more than 500 cells per μL: secondary outcome results from a randomised controlled trial. Lancet HIV. 2017;published online January 04, 2017.
  7. Durand M, Sheehy O, Baril JG, Lelorier  J, Tremblay  CL.  Association between HIV infection, antiretroviral therapy, and risk of acute myocardial infarction: a cohort and nested case-control study using Québec’s public health insurance database. J Acquir Immune Defic Syndr. 2011;57(3):245-253.
  8. Triant VA, Lee  H, Hadigan  C, Grinspoon  SK.  Increased acute myocardial infarction rates and cardiovascular risk factors among patients with human immunodeficiency virus disease. J Clin Endocrinol Metab. 2007;92(7):2506-2512.
  9. Crane HM, Paramsothy P, Drozd DR,et.al. Types of Myocardial Infarction Among Human Immunodeficiency Virus–Infected Individuals in the United States. JAMA Cardiol. Published online January 04, 2017. doi:10.1001/jamacardio.2016.5139
  10. Burstein HJ, Schrag D. Biosimilar Therapy for ERBB2 (HER2)–Positive Breast Cancer Close Enough?. JAMA. 2017;317(1):30-32. doi:10.1001/jama.2016.18979
  11. Rugo HS, Barve A, Waller CF, et. al. Effect of a Proposed Trastuzumab Biosimilar Compared With Trastuzumab on Overall Response Rate in Patients With ERBB2 (HER2)–Positive Metastatic Breast Cancer. JAMA. 2017;317(1):37-47. doi:10.1001/jama.2016.18305
  12. Therasse et al, “New response evaluation criteria in solid tumors: Revised RECIST guideline (version 1.1),” European Journal of Clinical Oncology, pp. 45: 228‐247, 2009.
  13. Hong Chen et al. Living near major roads and the incidence of dementia, Parkinson’s disease, and multiple sclerosis: a population-based cohort study. The Lancet, 2017 DOI: 10.1016/S0140-6736(16)32399-6
  14. Griffin NW, Ahern PP, Cheng J,et.al. Prior Dietary Practices and Connections to a Human Gut Microbial Metacommunity Alter Responses to Diet Interventions. Cell Host & Microbe, 2016; DOI: 10.1016/j.chom.2016.12.006
  15. Luciano M, Corley J, Cox SR, et.al. Mediterranean-type diet and brain structural change from 73 to 76 years in a Scottish cohort. Neurology. Published online January 4 2017 doi:10.1212/WNL.0000000000003559