Primecuts – This Week In The Journals

June 20, 2016

Love_vs__HateBy Janice Jang, MD

Peer Reviewed

On Sunday, June 12th a safe haven for the L.G.B.T. community in Orlando bore witness to the deadliest mass shooting in the United States and the worst act of terrorism in our country’s history since 9/11.   The 29-year-old gunman, Omar Mateen, entered the gay nightclub filled with hundreds of people celebrating the club’s weekly Latin Night, and single-handedly turned the scene into a deadly massacre, leaving 49 people dead and 53 wounded [1].  In the aftermath of the shooting, America is once again forced to confront homophobia, terrorism, and gun control, fueling political tensions as we draw closer to the presidential election.  Although we cannot prevent every act of gun violence or terrorism, policymakers can certainly make it harder and rarer by banning civilians from purchasing semi-automatic assault rifles.  The use of such lethal weapons has no place outside of the battlefields in the context of military operations. With that, we turn to some of this week’s published medical advancements that may contribute to reducing the morbidity and mortality in patients throughout our clinical practice.

Long-Acting Opioids Are Associated with Increased Mortality in Patients with Chronic Noncancer Pain

A retrospective cohort study of patients with chronic noncancer pain and no evidence of end-of-life care revealed that prescription of long-acting opioids, when compared with control medications, was associated with a significantly increased risk of all-cause mortality, including deaths from causes other than overdose [2].  Patients were included if they were less than 75 years of age and had a diagnosis of chronic pain in the last 90 days without evidence of cancer, other fatal diseases, or palliative care involvement.  Study drugs were sustained release morphine, controlled release oxycodone, transdermal fentanyl, and methadone.  Control drugs were gabapentin, pregabalin, carbamazepine or low-dose cyclic antidepressants. The end point was death occurring during the follow-up; all out-of-hospital deaths were further classified as unintentional medication overdose, cardiovascular, respiratory, or other injury. Statistical analysis revealed that all-cause mortality was 1.64 times greater in the study group compared to the control group.  There was 1.90 times greater risk of out-of-hospital deaths, 2/3 of the excess deaths were due attributed to causes other than unintentional overdose. In the setting of increasing opioid-related deaths in the U.S, this study reinforces the importance of using non-opioid agents for the treatment of chronic noncancer pain. While non-opioid agents are attractive for this reason, the analgesic effect of nonopioids and the overdose potential of those drugs need further review when determining opioid sparing pain regimens.

Early Aspirin Administration to At-Risk Patients Does not Reduce Risk of ARDS

Acute respiratory distress syndrome, an inflammatory process mediated by alveolar-capillary membrane injury and hypoxemic respiratory failure, remains difficult to treat, with mortality in severe ARDS as high as 40-50%.  Researchers are now focusing on earlier interventions to minimize the risk of developing ARDS or prevent severe consequences in high-risk patients.  Based on prior experimental data showing platelet dysfunction in the development of ARDS [3], early aspirin administration was tested as a preventive and therapeutic strategy.  A double-blind, randomized control trial of 390 patients from 16 medical centers from across the US was conducted.  Inclusion criteria included age 18 years or older, patients admitted through the emergency department with high risk for developing ARDS based on the lung injury prediction score [4].  A loading dose of 325 mg of aspirin was given, followed by 81 mg or placebo within 24 hours of presentation and administered daily for a total of 7 days or until death.  Primary outcome was the development of ARDS by hospital day 7. Secondary outcomes included ventilator-free days, hospital and ICU length of stay, 28-day and 1-year survival, and change in serum biomarkers associated with ARDS.  Among at-risk patients presenting to the ED, the use of aspirin compared with placebo did not reduce the risk of ARDS at 7 days, nor did it have any effects on the secondary clinical outcomes [5]. Despite the increase in knowledge about the pathophysiology of ARDS, preventive strategies and treatment options remain limited. Our best options to date focus on the early recognition of ARDS and implementing mechanical ventilation strategies to prevent lung injury including reliable prediction models and ventilators that help reduce human error in urgent situations.

T2DM Patients Treated with Empagliflozin have Lower Risk of Adverse Cardiovascular Events when Compared with Placebo

More than one-third of patients with type 2 diabetes mellitus (T2DM) develop kidney disease, which is associated with increased mortality.  Despite intensive glycemic control and renin-angiotensin-aldosterone system blockade, T2DM patients remain at increased risk for cardiorenal complications.  In the EMPA-REG OUTCOME trial, researchers investigated the effect of empagliflozin, a selective sodium-glucose cotransporter 2 inhibitor, on cardiovascular outcomes and microvascular outcomes in type 2 diabetics. Empagliflozin reduces serum glucose by increasing urinary glucose excretion.  It has been associated with lowering hemoglobin A1C in T2DM, including those with stage 2 or 3a CKD, reductions in weight and blood pressure, and decreased intraglomerular pressure.  The study examined 7020 patients diagnosed with T2DM with comorbid cardiovascular disease and a glomerular filtration rate of at least 30.  Patients were randomly assigned to either the treatment group (empagliflozin at a dose of 10 mg or 25 mg) or placebo once daily in addition to standard care.  The median duration of treatment was 2.6 years and the median observation time was 3.1 years.  Of note, 80.7% of the patients were taking either an ACE-I or ARB at baseline. Primary outcome was a composite of three major adverse cardiovascular events: first occurrence of death from cardiovascular causes, nonfatal MI, or nonfatal stroke.  There was a significantly lower risk of cardiovascular outcomes in the pooled empagliflozin group than in the placebo group.  Among patients with T2DM who were at high risk for cardiovascular events, the use of empagliflozin was associated with a significantly lower risk of microvascular outcome events (hazard ratio 0.61), lower risk of progression to macroalbuminuria (hazard ratio 0.62) or clinically relevant renal outcomes (i.e. doubling of serum creatinine and initiation of CRRT; hazard ratio 0.54) than placebo when added to standard care.  Equivalent results were seen consistently across the two doses [6].  Though the high cost of the drug may not be affordable for many patients, the cost-benefit analysis of this anti-hyperglycemic medication may be of interest when considering decreased rates of cardiovascular events and worsening nephropathy.

Liraglutide Confers Lower Rate of Adverse Cardiovascular Events than Placebo in T2DM

Liraglutide is an analogue of human glucagon-like peptide 1 (GLP-1), which was approved for treatment of type 2 diabetes mellitus to lower glucose levels.  It has been associated with slight reductions in weight and blood pressure as well as an increase in heart rate.  In 2010, the Liraglutide Effect and Action in Diabetes: Evaluation of Cardiovascular Outcome Results (LEADER) trial was initiated to evaluate the long-term cardiovascular effects of liraglutide. A multicenter, double-blind placebo-controlled trial was performed on 9340 patients with type 2 diabetes who were at high risk for cardiovascular disease and had a baseline HA1C level of at least 7%.  The majority of the patients had established cardiovascular disease (coronary artery disease, chronic heart failure, cerebrovascular disease, or peripheral vascular disease), chronic kidney disease of stage 3 or higher, or both.  Participants were randomly assigned to receive liraglutide or placebo, and the medial follow-up was 3.8 years in each group.  The median daily dose of liraglutide was 1.78 mg.  The primary composite outcome in the time-to-event analysis was the first occurrence of death from cardiovascular causes, nonfatal MI, or nonfatal stroke.  The liraglutide group was found to have a lower risk of the primary composite outcome (NNT = 66) and lower risk of death from any cause (NNT = 98) than did those in the placebo group.   Regarding the drug’s safety profile, the rate of neoplasms was higher in the group treated with liraglutide when compared to placebo.  Notably, there were 13 patients (0.3%) in the experimental group who developed pancreatic carcinoma and 5 patients (0.1%) in the control group, resulting in a statistically nonsignificant difference with a p-value of 0.06 [7].  But perhaps the most influential deterrent in utilizing this drug is the high cost, which may cause patients to seek alternative antihyperglycemic agents.


The Relationship of Parathyroidectomy and Bisphosphonates with Fracture Risk in Primary Hyperparathyroidism: an Observational Study. 

In Annals this week, an observational retrospective study shows that bisphosphonates are associated with an increase in bone mineral density but not a reduced fracture risk in patients with primary hyperparathyroidism.  Parathyroidectomy was associated with reduced fracture risk regardless of the patient’s candidacy for surgery based on consensus guidelines [8], suggesting that clinicians should consider surgery referrals more favorably for those who meet criteria.

Cardiovascular Events Associated with Use of Tyrosine Kinase Inhibitors (TKI) in Chronic Myeloid Leukoemia

Also in Annals, a retrospective cohort study out of Sweden showed tyrosine kinase inhibitors were associated with an increased risk for arterial and venous vascular events in patients being treated for chronic myeloid leukemia with TKI [9].  Given that the control group was an age-matched and sex-matched sampling from Sweden’s registry of the general citizen population; it is unclear whether this increased risk for adverse cardiovascular events is attributable to TKI or CML alone.

Rituximab and Dose-dense Chemotherapy for Adults with Burkitt’s lymphoma

In a multicenter randomized control trial of 257 adult patients with Burkitt’s lymphoma, the addition of rituximab to the lymphoma malin B chemotherapy regimen (an intensive and complicated regimen consisting of cyclophosphamide, vincristine, prednisone, doxorubicin, high-dose methotrexate, high-dose cytarabine, and intrathecal ara-C) was found to result in improved event-free survival (EFS) and overall survival (OS) when compared with those not given rituximab [10]. Due to the need for early induction data analysis was done on all patients, regardless of the final histological diagnosis; therefore these findings require a reader’s discretion prior to using Rituximab on HIV-neg, histologically confirmed Burkitt’s lymphoma.

Dr.  Janice Jang is a 1st year resident at NYU Langone Medical Center

Peer reviewed by Kerrilynn Carney, MD, chief resident, internal medicine, NYU Langone Medical Center

Image courtesy of Wikimedia Commons 


  1. Alvarez, Lizette, and Richard Perez-Pena. “Praising Isis, Gunman Attacks Gay Nightclub, Leaving 50 Dead in Worst Shooting on U.S. Soil.” New York Times 13 June 2016: A1(L).
  2. Ray WA, Chung CP, Murray KT, et al. Prescription of Long-Acting Opioids and Mortality in Patients with Chronic Noncancer Pain. JAMA. 2016;315(22):2415-2423.
  3. Yadav  H, Kor  DJ.  Platelets in the pathogenesis of acute respiratory distress syndrome. Am J Physiol Lung Cell Mol Physiol. 2015;309(9):L915-L923.
  4. Bauman ZM, Gassner MY, Coughlin MA, et al. Lung Injury Prediction Score Is Useful in Predicting Acute Respiratory Distress Syndrome and Mortality in Surgical Critical Care Patients. Critical Care Research and Practice, vol. 2015, Article ID 157408, 8 pages, 2015.
  5. Kor DJ, Carter, RE, Park PK, et al. Effect of Aspirin on Development of ARDS in At-Risk Patients Presenting to the Emergency Department: The LIPS-A Randomized Clinical Trial.AMA. 2016;315(22):2406-2414.
  6. Wanner C, Inzucchi SE, Lachin JM, et al. Empagliflozin and Progression of Kidney Disease in Type 2 Diabetes. NEJM 2016.
  7. Marso SP, Daniels GH, Brown-Frandsen K, et al. Liraglutide and Cardiovascular Outcomes in Type 2 Diabetes. NEJM. 2016.
  8. Yeh MW, Zhou H, Adams AL, et al. The relationship of parathyroidectomy and bisphosphonates with fracture risk in primary hyperparathyroidism: an observational study. Ann Intern Med. 2016;164(11):715-723.
  9. Dalen T, Edgren G, Lambe M, et al. Cardiovascular Events Associated with Use of Tyrosine Kinase Inhibitors in Chronic Myeloid Leukoemia: A population-based cohort study. Ann Intern Med. 2016.
  10. Ribrag V, Koscielny, Salles G, et al. Rituximab and dose-dense chemotherapy for adults with Burkitt’s lymphoma: a randomized, controlled, open-label, phase 3 trial. The Lancet. 11-17 June 2016, Vol. 387(10036): 2402-2411.