Primecuts – This Week In The Journals

May 31, 2016

Red_crabsBy Jung-Eun Ha, MD

Peer Reviewed

These past few weeks have seen some very interesting news items. The first genitourinary reconstructive (penile) transplant in the US was performed by surgeons at Massachusetts General Hospital earlier this month.[1] The patient lost his organ to penile cancer in 2012 and has thus far had an uneventful post-operative course, including the resumption of normal urination. This surgery follows two earlier penile transplants performed abroad. The first transplant was in China in 2005, but the transplant had to be removed 2 weeks later due to psychological distress for the patient and family. In 2014, a South African patient underwent a transplant and was able to successfully father a daughter the following year.

On May 13, Pfizer announced that it would strictly regulate that certain of its medications not be used in executions.[2] These medications include sedatives like midazolam, propofol, and hydromorphone, paralytics such as pancuronium bromide, rocuronium, and vecuronium bromide, and potassium chloride. This move is seen as a win for those who oppose capital punishment. The 20-plus states that use more than one drug for execution will now likely find it harder to secure the necessary medications, though there are 6 other states that use only one drug, phenobarbital, which is not regulated by Pfizer. To get around such regulations, some states have increasingly been using compounding pharmacies. Some have also passed laws allowing non-pharmacological methods of execution such as firing squad, gas chamber, or electric chair.

Finally, in non-medical news, the beaches of Southern California have been covered with tiny red crabs for a second straight year.[3] Known as tuna crabs as they are favored by some tuna species, they have been found to be carried from their natural habitats in Mexican waters to California likely due to the El Nino system. Unfortunately they are not edible for humans as their diet mainly consists of toxin-producing planktons.

Now let’s turn to the most interesting recently-released articles in medicine.

Indacaterol and glycopyrronium vs. salmeterol and fluticasone in reducing COPD exacerbations.

Recent guidelines recommend using long-acting beta-agonists (LABA) plus inhaled glucocorticoids or long acting muscarinic antagonist (LAMA) to reduce COPD exacerbations. The year-long randomized, double blind, multicenter, noninferiority FLAME study published in NEJM was conducted to answer which combinations might work better.[4] 1680 patients received the LABA indacaterol and the LAMA glycopyrronium, and 1682 patients received the LABA salmeterol and the glucocorticoid fluticasone. Patients who received indacaterol and glycopyrronium had 11% less annual COPD exacerbations compared to those who received salmeterol and fluticasone (p=0.003), and a longer time to the first exacerbation as well (71 days vs. 51 days, p<0.001). As previous studies[5] have shown that use of a LABA plus glucocorticoids had a stronger effect on patients with higher eosinophil counts, patients were further divided into groups with eosinophil counts lower than and equal/greater than 2%. Incidence of adverse effects and deaths were similar between the two treatment groups although incidence of pneumonia was 3.2% in the LABA plus LAMA group and 4.8% in the LABA plus glucocorticoids group. The study might have favored the LABA plus LAMA regimen as this used once-daily dosing, whereas dosing was twice-daily for the LABA plus glucocorticoid regimen. The study also used electronic flags for the outcome variable of COPD exacerbation, including all severities of exacerbations, which would have pushed the result towards noninferiority. The study is the last of the IGNITE study series sponsored by Novartis, which evaluates indacaterol and glycopyrronium.

Ticagrelor vs. aspirin after ischemic stroke or transient ischemic attack.

After ischemic strokes and transient ischemic attacks (TIAs), the risk of subsequent ischemic attacks is high within the first 90 days. Aspirin is commonly used for prevention in these settings, but even on aspirin, the recurrent stroke rate is about 10 to 15% during the first 90 days. Aspirin also leads to an increased risk of GI bleeding. Ticagrelor is an antiplatelet that directly binds the P2Y12 receptor on platelets and is hypothesized to be more effective and selective than aspirin. Recently the NEJM published the results of the Acute Stroke or Transient Ischaemic Attack Treated with Aspirin or Ticagrelor and Patient Outcomes (SOCRATES) trial,[6] a multicenter, double-blind, parallel-group trial that randomized patients with non-cardioembolic ischemic stroke or TIA into ticagrelor or aspirin monotherapy within 24 hours after symptom onset, provided that they did not receive thrombolytic therapy. The primary composite end points, which included stroke, myocardial infarction, or death, occurred in 6.7% of patients who received ticagrelor vs. 7.5% of patients who received aspirin (p=0.07). The main secondary end point of ischemic stroke occurred in 5.8% of the ticagrelor group vs. 6.7% of the aspirin group (p=0.046). The major bleeding at any location occurred in 0.5% in the ticagrelor group vs. 0.6% in the aspirin group (NS), while intracranial bleeds occurred in 0.2% in the ticagrelor group vs 0.3% in the aspirin group. Early treatment termination occurred in 17.5% of participants in the ticagrelor group vs 14.7% of those in the aspirin group, mainly due to the side effect of dyspnea (6.2% vs 1.4%). The study was limited as patients at highest risk for stroke were mostly excluded, as they would have undergone further interventions and were likely already receiving more than multiple drug therapy. The study also excluded those who received thrombolytics, thereby further limiting generalizability. More studies need to be done to find a better agent to prevent recurrent ischemic events in larger patient populations.

Antacid therapy in idiopathic pulmonary fibrosis (IPF).

The incidence of gastroesophageal reflux disease (GERD) in patients with IPF is higher than in the general population. This may be due to the increased recoil of the fibrotic lung that could dilate the lower esophageal sphincter. GERD may also exacerbate IPF from chronic micro-aspiration and associated inflammation. Based on retrospective studies that showed slowed progression of IPF in patients who received antacids, such treatment is now recommended in the IPF treatment guidelines.

In this post-hoc analysis of 624 patients with IPF in three large controlled trials published in the Lancet,[7] randomized antacid therapy did not yield clinically significant improvements in outcomes after 52 weeks. In the Kaplan-Meier analysis, patients who received antacid treatment had similar disease progression at 1 year compared with placebo (37.8% vs. 40.5%; p=0.40). The rates of all-cause mortality and IPF-related mortality were similar between the treatment and control groups. Adverse gastrointestinal effects were similar between the two groups as well after stratifying by baseline FVC. On the other hand, in patients with FVC less than 70%, infections (including pneumonia) were significantly higher with antacid therapy than with no antacid therapy (74% vs. 62%; p=0.017). The difference from previous studies may be due to exclusion of patients with advanced diseases and those who are listed for potential transplantation. The study also had a relatively small sample size and was underpowered to detect any meaningful subtle differences. On the other hand, previous retrospective analyses may have been affected by lead-time bias, leading to slower disease progression with antacid therapy. Given these results, individualized approach to IPF treatment may be ever more necessary.

Association between environmental toxins and ALS.

Amyotrophic lateral sclerosis (ALS) is a progressive degeneration of motor neurons, and some hypothesize that toxic exposures in addition to genetic susceptibility may lead to this condition. A case control study[8] published in JAMA Neurology evaluated 156 cases and 128 controls in Michigan from 2011 to 2014. In addition to survey data of self-reported exposures to occupational and residential toxins, the study also measured serum concentration of 122 pollutants, more than any other previous studies looking at this issue. Exposure window was also considered, such as within the last 10 years, between 10 to 30 years, more than 30 years prior, or at least once in the past. The study found that reported exposure to toxins was significantly associated with ALS (OR=5.09, p=0.002). Military service with likely exposures to chemicals was also associated with ALS. Multivariable analysis of the serum concentration of pollutants showed that 2 OCPs (organochlorine pesticides), 2 PCBs (polychlorinated biphenyls), and 1 BFR (brominated flame retardant) were all significantly associated with development of ALS. There was modest concordance between survey data and measured data giving confidence to the previous survey data. These results suggest that controlling modifiable risk factors for ALS may translate into reductions in incidence of ALS.

Mini cuts:

A cohort study looked at late mortality (from 1 month to 2 years after admission) for sepsis in Medicare populations.[9] Compared with adults not in the hospital, patients with sepsis had a 22% absolute increase in late mortality. Compared with patients admitted to the hospital with non-sepsis infections or sterile inflammatory conditions, patients with sepsis had a 10% increase in late mortality.

1% relative reductions in smoking prevalence and mean packs-smoked are associated with 0.118% (p < 0.001) and 0.108% (p < 0.001) reductions in per capita healthcare expenditures, respectively.[10] A 10% relative reduction in smoking in every state is predicted to result in a $63 billion reduction in healthcare expenditures in the following year.

The American Community Survey (ACS) data were evaluated for the insurance and Indian Health Service (IHS) coverage among Native Americans one year after the Affordable Care Act (ACA) was mandated.[11] The ACA was associated with significant coverage increases for Native Americans, primarily in Medicaid expansion states, where Medicaid expansion is likely supplementing rather than replacing IHS.

Physician and surrogate decision makers were found to have incongruous views regarding prognosis in 53% of ICU cases.[12] In 28% of cases this was due to misunderstandings by surrogates and differences in beliefs. Surrogates had more optimistic beliefs than physicians, including religious beliefs and beliefs that the patient has unique strengths unbeknownst to the physician, out of their need to maintain hope for the patient.

Dr. Jung-Eun Ha is an  intern at NYU Langone Medical Center

Peer reviewed by Anish B. Parikh, MD, Chief Resident, Medicine, NYU Langone Medical Center

Image courtesy of Wikimedia Comons


[1] Massachusetts General Hospital. First Genitourinary Vascularized Composite Allograft (Penile) Transplant in the Nation Performed at Massachusetts General Hospital May 16, 2016. Accessed on May 18, 2016

[2] Eckholm E. Pfizer Blocks the Use of Its Drugs in Executions. The New York Times. May 13, 2016. Accessed on May 18, 2016

[3] Reuters. Tiny red crabs are back on California beaches. Scientists blame El Niño. The Washington Post. May 17, 2016. Accessed on May 18, 2016.

[4] Wedzicha JA, Banerji D, Chapman KR, Vestbo J, Roche N, Ayers T, et al. Indacaterol–Glycopyrronium versus Salmeterol–Fluticasone for COPD. NEJM. Published Online: May 15, 2016 (DOI: 10.1056/NEJMoa1516385).

[5] Pavord ID, Lettis S, Locantore N, et al. Blood eosinophils and inhaled corticosteroid/ long-acting β-2 agonist efficacy in COPD. Thorax 2016; 71: 118-25.

[6] Johsnton SC, Amarenco P, Albers GW, Denison H, Easton D, Evans SR, et al. Ticagrelor versus Aspirin in Acute Stroke or Transient Ischemic Attack. NEJM. Published Online: May 10, 2016 (doi: 10.1056/NEJMoa1603060).

[7] Keruter M, Wuyts W, Renzoni E, Koschel D, Maher TM, Kolb M, et al. Antacid therapy and disease outcomes in idiopathic pulmonary fibrosis: a pooled analysis. Lancet. 2016; 4(5):381-389.

[8] Su F-C, Goutman SA, Chernyak S, Mukherjee B, Callaghan BC, Batterman S, Feldman EL. Association of Environmental Toxins With Amyotrophic Lateral Sclerosis. JAMA Neurol. Published Online May 9, 2016 (doi:10.1001/jamaneurol.2016.0594).

[9] Prescott HC, Osterholzer JJ, Langa KM, Angus DC, Iwashyna TJ. Late mortality after sepsis: propensity matched cohort study. BMJ. 2016; 353: i2375. Published Online: May 17, 2016 (

[10] Lightwood J, Glantz SA. Smoking Behavior and Healthcare Expenditure in the United States, 1992–2009: Panel Data Estimates. PLoS Med. 2016;13(5): e1002020. Published Online: May 10,2016 (doi:10.1371/journal.pmed.1002020)

[11] Frean M, Shelder S, Rosenthal MB, Sequist TD, Sommers BD. Health Reform and Coverage Changes Among Native Americans. JAMA Intern Med. Published online May 16, 2016. (doi:10.1001/jamainternmed.2016.1695)

[12] White DB, Ernecoff N, Buddadhumaruk P, Hong S, Weissfeld L, Curtis JR, Luce JM, Lo B. Prevalence of and Factors Related to Discordance About Prognosis Between Physicians and Surrogate Decision Makers of Critically Ill Patients. JAMA. 2016;315(19):2086-2094.